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Abstract Introduction Malnutrition in children with sickle cell anemia (SCA) is associated with higher rates of hospitalizations and early mortality, particularly in low-income settings such as northern Nigeria. However, there are no established guidelines for the optimal management of malnutrition in children with SCA, and key parameters such as caloric targets and treatment duration have yet to be defined. Our feasibility trial demonstrated that nutritional supplementation with ready-to-use therapeutic food (RUTF), with or without moderate fixed-dose hydroxyurea (20 mg/kg/day), is safe and supports weight gain in children with SCA and severe malnutrition (body mass index [BMI] z-score < −3.0) (Abdullahi et al., Blood Advances, 2023). However, 61% (n = 66 of 108) of children remained severely malnourished after the initial 12-week intervention. We therefore conducted a 12-week, single-arm extension to assess whether increasing caloric intake and treatment duration would improve recovery and to identify predictors of nutritional response. Methods We conducted a 12-week, single-arm extension of a multicenter randomized controlled feasibility trial (NCT03634488) evaluating nutritional management in children aged 5–12 years with SCA in northern Nigeria. Children who remained severely malnourished (BMI z-score < −3.0) after the initial 12-week intervention were enrolled in the extension phase. Unlike the parent trial, which provided RUTF as a supplement, the extension phase provided RUTF as a complete nutritional replacement at 2,000–2,500 kcal/day. All participants received moderate fixed-dose hydroxyurea. Follow-up visits occurred at weeks 4, 8, and 12 of the extension (corresponding to weeks 16, 20, and 24 since initial enrollment). The primary outcome was nutritional recovery, defined as BMI z-score ≥ −3.0. Results Participant Characteristics: Of 108 children with SCA and severe malnutrition who completed the initial 12-week intervention, 66 (61%) remained severely malnourished (BMI z-score < −3.0) and were enrolled in the 12-week extension phase. Change in Nutritional Status from 12 to 24 Weeks: Among the 66 children enrolled in the extension, 11 (17%) achieved a BMI z-score of > -3.0 at week 24. The mean change in BMI z-score during the 12-week extension was 0.13 (SD 0.47). In a linear regression model, female sex was associated with a greater improvement in BMI z-score from weeks 12 to 24 (β = 0.262, p = 0.032). No significant associations were observed for age, hemoglobin concentration, treatment group, or the 12-week BMI z-score. Among the extension cohort, in a penalized logistic regression model, a higher 12-week BMI z-score remained associated with recovery at 24 weeks (OR = 14.44, p = 0.039). Predictors of Treatment Success: Children who recovered by 12 weeks had greater early weight gain at 4 weeks from enrollment than those recovering by 24 weeks, with the smallest early gains seen in children who never recovered (p < 0.001). Logistic regression analysis, including all 108 participants (combining the initial and extension phases), revealed that younger age (OR = 1.39, p = 0.006) and early change in BMI z-score during the first 4 weeks were associated with treatment success (OR = 12.38, p < 0.01). Conclusions Baseline BMI z-score and early weight gain during nutritional intervention are important indicators of treatment response. A 4-week progress assessment may help identify children who may benefit from closer clinical evaluation and address socioeconomic barriers. While early weight gain predicts recovery, our findings and prior work in younger children without SCA suggest that early non-response is not a definitive indicator of treatment failure (Cazes et al., PLOS Glob Public Health, 2025). However, even with extended high-calorie RUTF, only a small proportion (17%) of children recovered, suggesting that delaying treatment intensification until 12 weeks may be too late for many. Because both clinical and socioeconomic factors influence malnutrition in children with SCA, optimizing outcomes will require tailored interventions. Our ongoing and future work focuses on integrating nutritional education and vocational training into malnutrition prevention and treatment programs for children with SCA.