This study investigated responses to retreatment with rituximab in chronic immune thrombocytopenic purpura (ITP) patients. Treatment with rituximab in chronic ITP patients induces long-lasting responses in ∼30% of patients but even these patients may relapse. Twenty patients who had achieved a response to rituximab and relapsed were retreated with rituximab (375 mg/m2× 4); this data was analyzed retrospectively. Subsequently, 16 patients were prospectively randomized to receive rituximab with cyclophosphamide, vincristine and prednisone (R-CVP) or double dose rituximab (DDR). Retreatment with standard dose rituximab demonstrated responses similar to initial rituximab treatment in 15 of 20 patients. Neither of the two more intensive regimens (R-CVP, DDR) induced responses in any patient who had previously failed to respond to rituximab nor induced substantially longer-lasting responses among previous responders. No additional toxicity was noted with the DDR regimen, whereas R-CVP was not well tolerated. These results suggest that retreatment with standard dose rituximab induces similar responses in 75% of previously responding patients and is well tolerated. Neither combining rituximab with CVP nor doubling the dose of rituximab increased the response rate. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc.