Initial therapy of chronic GVHD (cGvHD) has not changed for over three decades, despite limited efficacy and long-term toxicity. We have previously shown in a small pilot study the feasibility of rituximab-based first-line therapy of cGVHD. To better assess safety and efficacy, we now evaluate 69 patients that received rituximab as part of their initial treatment. Median follow-up for surviving patients was 47 (11-81) months. Resolution of cGVHD occurred in 49 patients with median time to IST discontinuation of 349 (138-920) days. The cumulative incidence (CI) of cGHVD resolution was 41%, 69 and 77% at 1-, 2- and 3-years, respectively. No systemic corticosteroids were used in 27 patients, and 67% received ≤ 10 mg/kg cumulative exposure. Overall survival (OS) at 1-, 2- and 3-years following cGVHD diagnosis was 87, 79 and 77% respectively; corresponding rates of non-relapse mortality (NRM) were 10%, 16 and 19%. The probability of being alive and free of cGVHD at 1-, 2-, and 3-years was 36, 55, and 57% respectively. This study demonstrates the feasibility and efficacy of rituximab-based first-line cGVHD treatment. This approach demonstrates significant activity and avoids long courses of corticosteroids in most patients.