To assess the Hb F response to hydroxyurea (HU) in Yemeni sickle cell disease, 86 patients attending hospitals in Sana'a City, Yemen, were studied. Group I (short-term follow-up, n = 21) were treated with 500 mg/day HU for 3-6 months; group II (long-term, n = 26) were treated with 500 mg/day HU for 8-48 months; group III were untreated (n = 39). Hb F levels were monitored using cation exchange high performance liquid chromatography (HPLC). Group I showed significant increase in Hb F level after treatment (10.0 ± 5.8 to 13.8 ± 5.9%). Hb F level increased significantly with treatment in group II when compared to group III. The increase in Hb F level was associated with increased hemoglobin (Hb) levels. Hydroxyurea, even at a low dose, appears to be effective in raising Hb F levels in Yemeni sickle cell disease patients without any association of major side effects. Further study is required to investigate its maximum tolerated dose and its effects on increase in Hb F, frequency of acute crisis and any long-term toxicity.