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Introduction: Hydralazine-induced lupus (HIL) is an uncommon complication with various presentations. In critically ill patients, diagnosis is challenging due to overlap with infection, malignancy, or autoimmune diseases. We report a case of a patient who developed a lymphocyte-predominant pleural effusion, ultimately diagnosed as drug-induced lupus from chronic hydralazine therapy. Description: An elderly patient presented with acute periumbilical pain and vomiting after hemodialysis. The patient was on hydralazine 100 mg TID. Computer tomography (CT) abdomen showed umbilical hernia and incidental moderate loculated left pleural effusion; CT chest confirmed left lung collapse with loculated severe effusion. Thoracentesis revealed pleural fluid with WBC 317 (86% lymphocytes), negative Adenosine Deaminase and acid-fast bacilli, ruling out tuberculosis and malignancy despite prior colon cancer history. Patient initially was scheduled for Video-Assisted Thoracic Surgery but was later converted to thoracotomy given the thick adhesions. Pleural fluid cytology and surgical pathology are negative for malignancy. Autoimmune serologies showed negative ANA and positive antihistone antibodies (5.4). Findings strongly indicated HIL with lymphocyte-predominant pleural effusion. Discussion: This case highlights a unique case of lymphocyte-predominant pleural effusions, usually linked to tuberculosis, malignancy, or autoimmune diseases. In drug-induced lupus (DIL) pleural involvement is a known manifestation, often presenting as an exudative effusion with high lymphocytes. Hydralazine, a trigger of DIL, can cause serositis including pleuritis, as in this patient. Despite malignancy concerns, absence of neoplastic cells, chronic inflammation on pathology, and positive anti-histone antibodies confirmed HIL. The absence of ANA antibodies make this case even more unique. HIL risk is dose-dependent, ~5.4% at 100 mg/day and 10.4% at 200 mg/day, with slow acetylators and women at higher risk. Pleuritis occurs in < 5% of HIL cases but can be the sole feature. Early recognition and stopping the drug avoid unnecessary interventions and ensure resolution. This case stresses considering medication causes in unexplained effusions, especially with high-dose hydralazine. AI has been used to effectively summarize this paper.