This study aimed to evaluate the efficacy and safety of the fludarabine-cyclophosphamide-rituximab regimen for young physically fit patients with chronic lymphocytic leukemia in the "real-life" setting. We specifically focused on the impact of dose reduction on patient outcomes. The patient cohort consisted of 128 patients with chronic lymphocytic leukemia (≤70 years) treated at 10 Israeli centers with front-line fludarabine-cyclophosphamide-rituximab. We defined reduced chemotherapy as two-thirds or less of the total indicated dose. Patients treated with rituximab were divided into two groups and compared: those who received full dosages of 375 mg/m2 or 500 mg/m2, and patients given less than six cycles with either dose. Overall and clinical complete response rates (92.8% and 70.4%), as well as toxicities and overall survival (median not reached at 6 years), were similar to other reported clinical trials, but progression-free survival was shorter (42.5 months). Almost 50% of patients had some dose reduction of chemotherapy, 21% receiving less than two-thirds of the indicated dose, while close to 30% did not complete six cycles of rituximab. Reduced doses of chemotherapy and rituximab were independently associated with shorter progression-free survival (hazard ratio 3.6, P<0.0001 for reduced chemotherapy; hazard ratio 2.5, P=0.003 for incomplete-treatment with rituximab). Achieving a complete response was associated with longer overall survival but was not linked to the given dose of chemoimmunotherapy. In younger physically fit patients, front-line fludarabine-cyclophosphamide-rituximab therapy in the "real-life" setting achieves long remissions (albeit shorter than in clinical trials) and prolonged overall survival. However, dose reductions are commonly administered and may impact outcome.