Background. Malaria prophylaxis is recommended for persons with sickle-cell disease (SCD) but the value of this has been questioned. The aim of this study was to find out if intermittent preventive treatment (IPT) with a fixed-dose combination of mefloquine-artesunate (MQAS) or sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) was more effective than daily proguanil for malaria prevention in subjects with SCD. Methods. Patients with SCD were randomized to receive daily proguanil, or IPT with either MQAS or SPAQ administered once every two months at routine clinic visits, and followed up for fourteen months. Findings. 270 SCD patients were studied, 90 in each group. Adherence to the IPT regimens was excellent but 57% of patients took less than 75% of their daily doses of proguanil. IPT was well tolerated, the most common side effects were vomiting and abdominal pain. Protective efficacy against malaria, compared to daily proguanil, was 61%(95%CI 3%-84%) for MQAS and 36%(40%-70%) for SPAQ. There were fewer outpatient illness episodes in children who received IPT than in the proguanil group. Conclusion. IPT with MQAS administered when sickle-cell disease patients come for routine clinic visits was well tolerated and more effective in preventing malaria than daily prophylaxis with proguanil.