Objective To compare the clinical efficacy between prednisone combined with mycophenolate mofetil or cyclophosphamide treatment in patients with severe IgA nephropathy. Methods A total of 84 patients with severe IgA nephropathy were treated with the prednisone combined with mycophenolate mofetil (MMF group, n=42) or cyclophosphamide (CTX group, n=42), separately. The initial dosage of prednisone was 40 mg/d, and the dose of MMF was 1.5 g/d in induction stage for 6 months, and 0.75~1.0 g/d in maintenance stage for 12 months. The dose of CTX was 0.8-1.0 g/month in induction stage, by intravenous infusion, for 6 months, and 0.8 -1.0 g/3 months in maintenance stage for 12 months. There was no difference in the basal state between the two groups. All patients were administered for 18 months. The clinical remission rate and the corresponding laboratory parameters were observed, including 24-hour urinary protein excretion, serum creatinine, serum albumin, total protein, and lipid changes. The side effects of treatment were also compared between the two groups. Results (1)The clinical remission rate in MMF group of 18 months (85.7%) was higher than that in CTX group (61.8%) (P<0.05). (2) By the end of observation period, 24-hour urinary protein excretion in patients of MMF group (0.6 ± 0.3) was significantly lower than that in patients of CTX group (1.4±0.5) (P<0.05), plasma albumin and total protein in patients of MMF group (43.2±4.3 and 70.2±8.1) was significantly higher than that in patients of CTX group (36.9±3.6 and 60.3±7.6) (P＜0.05). (3)Blood lipids in patients of MMF group were significantly reduced than before(P<0.05), while those in patients of the CTX group did not change (P>0.05). (4)The incidence of side effects: in patients of the MMF group (4.76%) was significantly lower than that in patients of the CTX group (P<0.05). Conclusions The clinical remission rate of prednisone with MMF is higher than that of prednisone with CTX in patients with severe IgA nephropathy. And the prednisone with MMF therapy reduces 24 h urine protein effectively, improves blood lipids and plasma albumin levels to maintain stable renal function. Moreover, the side effects in the group of MMF therapy are significantly lower than those in the group of CTX therapy.