Background: Severe anemia (hemoglobin <70 g/L) in pregnancy may increase the risk of maternal and perinatal mortality. Objectives: We assessed response to standard treatment with high-dose iron-folic acid for 90 d and single-dose (500 mg) mebendazole among severely anemic pregnant women in periurban Karachi, Pakistan. In addition, we evaluated the efficacy of 2 enhanced treatment regimens. Design: We screened pregnant women (n - 6288) for severe anemia and provided them all with the standard treatment. To test the efficacy of 2 additional treatments, women were randomly assigned to standard treatment alone (control) or with 100 mg mebendazole twice daily for 3 d or 90 d of daily multivitamins or both using a 2 × 2 factorial design. Results: Prevalence of severe anemia was high (10.5%) during pregnancy. Prevalence of geohelminths and malaria was low. Treatment response was defined as hemoglobin >100 g/L at the 90-d or >25 g/L at the 60-d follow-up visit. The standard-of-care treatment resulted in a response rate of 49% at follow-up, although an adherence of >85% elicited a higher response (67%). The effect of the additional treatments was weak. Although response was higher in the enhanced groups than for the standard treatment at the final assessment, the differences were not statistically significant. However, hemoglobin concentration increased significantly in all groups and was higher in the enhanced mebendazole group compared with the standard group (P < 0.05). Conclusions: Iron deficiency was high in this population, and the standard-of-care treatment resulted in a treatment response of 50%, although better treatment adherence showed a higher response. Multivitamins and the enhanced mebendazole regimen had a modest benefit over and above the standard treatment.