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Abstract Background Idiopathic multicentric Castleman disease (iMCD) is a rare, cytokine-driven disorder defined by lymphadenopathy, distinctive lymph node histopathology, and systemic inflammation. Diagnosis is challenging and requires exclusion of neoplastic, autoimmune, and infectious conditions with a similar clinical presentation. ACCELERATE, the largest iMCD registry, includes diagnostic ratings by expert clinicians and pathologists on the likelihood of iMCD using clinical, radiological, pathological, and laboratory findings for each patient. Discordant pathologic interpretations and clinical overlap often lead to patients being treated for iMCD by their physicians, even when expert review suggests an alternative diagnosis. We analyzed how patients without a clear iMCD diagnosis or with an alternative diagnosis responded to iMCD-directed therapies. Methods We identified patients in the ACCELERATE registry for whom the expert panel found a likely alternative diagnosis (“OtherDx”), such as an autoimmune disease or neoplasm, or an “Indeterminate” diagnosis, indicating insufficient data to confirm iMCD or alternative diagnoses. OtherDx patients were grouped into alternative diagnostic categories. We defined individual regimens as treatments initiated within two weeks of each other, then grouped regimens into broader therapeutic categories. We defined a clinical response as a ≥50% decrease in the proportion of abnormal symptoms and laboratory measures after regimen initiation. We considered responses durable if patients did not initiate additional regimens within one year of the index regimen. We compared responses to those in panel-confirmed iMCD patients. Results Of the 392 adult and pediatric patients in the registry with panel review, we classified 89 (23%) as OtherDx and 30 (8%) as Indeterminate. Among these 119 patients, 104 received treatment and 83 had sufficient data to assess responses (60 OtherDx, 23 Indeterminate). Of the 60 OtherDx patients, 50% (30/60) had no clear alternative diagnosis, 20% (12/60) had a hematologic neoplasm, 15% (9/60) had an autoimmune disorder, 10% (6/60) had discordant pathologic interpretation or insufficient biopsy, and 5% (3/60) had another lymphoproliferative disorder. Both OtherDx/Indeterminate patients and panel-confirmed iMCD patients were treated with similar medications. Siltuximab±corticosteroids (CS) was the most common regimen in both OtherDx/Indeterminate (50%, 52/104) and panel-confirmed iMCD cohorts (52%, 66/126). Among evaluable patients, 69% (57/83) of OtherDx/Indeterminate and 83% (103/124) of panel-confirmed iMCD patients achieved a clinical response. Clinical response rates for siltuximab±CS were 66% (29/44) vs 76% (45/59); chemotherapy 61% (11/18) vs 82% (27/33); tocilizumab±CS 67% (4/6) vs 57% (12/21); and anti-IL6+immunomodulators±CS 67% (6/9) vs 67% (10/15), respectively (all n.s.). Durable response rates were comparable between both groups: 38% (28/73) of OtherDx/Indeterminate and 59% (70/118) of panel-confirmed iMCD patients. Durable response rates for siltuximab±CS were 37% (13/35) vs 52% (27/52); chemotherapy 33% (5/15) vs 48% (14/29); tocilizumab±CS 50% (3/6) vs 47% (9/19); and anti-IL6+immunomodulators±CS 43% (3/7) vs 43% (6/14), respectively (all n.s.). Among OtherDx patients with no clear alternative diagnosis, 73% (22/30) achieved a clinical response, compared to 58% (7/12) with possible hematologic malignancy and 78% (18/23) with Indeterminate diagnosis. Durable response rates were 46% (12/26) for those with no clear alternative diagnosis, 40% (4/10) with possible hematologic malignancy and 40% (8/20) for Indeterminate diagnosis (all n.s.). Conclusions We found that patients thought to have iMCD in the community often benefit from iMCD-directed therapies even without expert-confirmed diagnosis. Over one-third of OtherDx/Indeterminate patients had a durable response to siltuximab, the only FDA-approved iMCD therapy. Many anti-IL6 inclusive regimens produced comparable response rates to those with clearer iMCD diagnoses. While these findings suggest that patients with iMCD-like features may respond to iMCD therapies and demonstrate how other lymphoproliferative and inflammatory diseases may share targetable pathophysiological features, this is not intended to recommend anti-IL6 therapy without iMCD diagnosis. Limitations of the registry analysis include small sample size, missing data, and the absence of randomization, which may impact interpretation of results.