We assessed the effectiveness of iron+folic acid for the treatment of severe anemia [hemoglobin (Hb) <70 g/L] and the efficacy of added multivitamins and/or anthelminthics among children aged 6-24 mo in periurban Karachi, Pakistan. The study design was a double blind, placebo-controlled, randomized trial of currently recommended daily iron (25 mg) and folic acid (100 μg) for 90 d with daily multivitamins [vitamin A (300 μg, as retinol palmitate), vitamin E (6 mg tocopherol equivalents), vitamin B-12 (0.9 μg), vitamin C (15 mg), riboflavin (0.5 mg)] and/or anthelminthics (100 mg mebendazole twice daily for 3 d) compared with placebos. Treatment response was defined as reaching a Hb concentration ≥100 g/L at the end of 90 d. The prevalence of severe anemia in the 9518 children screened was 5.7% and a total of 462 severely anemic children were enrolled in the study. Adherence to treatment was ~70% for iron+folic acid, ∼80% for multivitamins, and almost 100% for mebendazole. Children receiving iron+folic acid alone had a response rate of 38.7% at 90 d. The additional treatment with mebendazole or multivitamins did not significantly improve cure rates or change the Hb concentration over and above iron+folic acid treatment alone. Adherence to iron+folic acid of higher than the median resulted in a better treatment response rate of 50%. High-dose daily iron+folic acid performed as well as iron+folic acid with anthelminthics and multivitamins in the treatment of severe anemia in this setting. Higher adherence may be important in enhancing treatment impact.