Background: FCR results in durable responses in patients with previously untreated CLL. Previous reports suggest that dose-intensified rituximab increases response rates compared to standard-dose rituximab in patients with relapsed CLL. The effect of rituximab intensification of FCR in patients with previously untreated CLL is unknown. Methods: We evaluated the safety and efficacy of a modified FCR regimen with multiple-dose rituximab (FCR3) in 65 patients with previously untreated CLL. The FCR3 regimen consisted of six 28-day cycles of IV fludarabine (25 mg/m²/d) and cyclophosphamide (250 mg/m²/d) over 3 days. For cycle 1, rituximab was given at 375 mg/m² on day 1 and at 500 mg/m² on days 2-3. For cycles 2-6, rituximab was given at 500 mg/m² on days 1-3. Results were compared to a historical cohort treated with FCR. Results: The overall response rate to FCR3 was 97%. Forty-eight patients (75%) achieved CR, 10 (16%) achieved nPR, 4 (6%) achieved PR, and 2 (3%) did not respond to FCR3. Response rates were not significantly different from the historical FCR cohort. The median time to progression (TTP) for patients achieving CR, nPR and PR was 86 months, 49 months and not evaluable, respectively (P = 0.14 for CR vs. nPR). MRD negativity by flow cytometry was achieved in 62% of patients. Median TTP was 81 months, which was similar to the median TTP of 84 months with FCR (P = 0.63). Median OS was not reached, with 58% of patients still alive at a median survivor follow-up of 9.7 years (P = 0.58 compared to FCR). Thirty-one (65%) of those patients who achieved CR, 6 patients (60%) who achieved nPR and 1 patient (25%) who achieved PR are still alive. Grade 3-4 neutropenia, grade 3-4 thrombocytopenia and major infection were observed with 45%, 5% and 1.9% of FCR3 courses (not significant compared to FCR). Therapy-related MDS or AML developed in 7 patients (11%) (P < 0.01 compared to FCR) at a median of 32 months and accounted for 26% of all deaths. Conclusions: In patients with previously untreated CLL, FCR3 resulted in similar response rates, TTP and OS compared to a historical cohort of patients treated with FCR. FCR3 was associated with a significantly increased incidence of therapy-related MDS/AML, which warrants further evaluation. Clinical trial information: NCT00794820