Treatment of steroid refractory autoimmune hemolytic anemia (AIHA) is challenging especially with no evidence based consensus guide lines and limited resources. The aim of this study was to evaluate the efficacy of pulse cyclophosphamide therapy in patients with severe refractory warm AIHA. The prospective study was designed to evaluate the efficacy of pulse cyclophosphamide—1 g/month for four consecutive months—in 17 patients (10 males and 7 females) with severe refractory warm AIHA [13 primary AIHA and 4 (females) secondary to SLE], all studied patients failed to respond to high dose of steroid therapy ± azathioprine ± intravenous immunoglobulin ± oral cyclophosphamide. Mean hemoglobin level, reticulocytic count and direct antiglobulin test were assessed before and after cyclophosphamide treatment every month. After the 4th cycle of cyclophosphamide (82 %, 14 patients) achieved partial response while the remaining (17 %, 3 patients) showed no response, while after 6 months follow up 47 % (8 patients) show complete response, while 53 % (9 patients) showed partial response. The mean hemoglobin levels were significantly increased after the 1st, 2nd, 3rd and 4th months of pulse cyclophosphamide therapy when compared to before treatment (P<0.01, P<0.001, P<0.001 and P<0.001) respectively, and the mean reticulocyte (%) were significantly decreased after the 2nd, 3rd and 4th months (P<0.05, P<0.01 and P<0.001) respectively. We conclude that pulse cyclophosphamide therapy is well tolerated and induces good response in patients with severe refractory warm AIHA.