BACKGROUND: IgA nephropathy (IgAN) is not always benign, and some patients at high risk of end-stage renal disease (ESRD) experience a rapid decline in renal function. This study retrospectively examined the beneficial effects of cytotoxic therapy. METHODS: We identified 102 patients with progressive IgAN despite optimal conservative management. Of these, 31 who received cytotoxic therapy and 55 who were managed conservatively were included. RESULTS: Median eGFR and urinary protein-to-creatinine ratio (uPCR) at baseline did not differ between the groups (p = 0.475 and 0.259, respectively). Median GFR slope was also similar (p = 0.896). Cumulative renal survival was better in the cytotoxic therapy group than in the control group (p = 0.009). Cytotoxic therapy was associated with lower risk of progression to ESRD, independent of eGFR, uPCR, GFR slope and kidney histologic findings (HR 0.13, 95% CI 0.03-0.66). In the cytotoxic therapy group, the median GFR slope decreased from -7.8 (-10.5, -5.0) mL/min/1.73 m(2) per year to -3.4 (-5.1, -1.8) mL/min/1.73 m(2) per year after treatment (p < 0.001). Mortality was not observed, but infection requiring hospitalization occurred at similar rates in both groups (p = 0.886). CONCLUSIONS: Cytotoxic therapy attenuated the rate of GFR decline and was associated with a favorable renal outcome in patients with progressive IgAN.