The development of highly effective targeted agents for chronic lymphocytic leukemia offers the potential for fixed-duration combinations that achieve deep remissions without cytotoxic chemotherapy. This phase II study tested a combination regimen of obinutuzumab, ibrutinib, and venetoclax for a total of 14 cycles in both patients with treatment-naïve (n = 25) and relapsed or refractory (n = 25) chronic lymphocytic leukemia to determine the response to therapy and safety. The primary end point was the rate of complete remission with undetectable minimal residual disease by flow cytometry in both the blood and bone marrow 2 months after completion of treatment, which was 28% in both groups. The overall response rate at that time was 84% in treatment-naïve patients and 88% in relapsed or refractory patients. At that time, 67% of treatment-naïve patients and 50% of relapsed or refractory patients had undetectable minimal residual disease in both the blood and marrow. At a median follow-up of 24.2 months in treatment-naïve patients and 21.5 months in relapsed or refractory patients, the median progression-free and overall survival times were not yet reached, with only 1 patient experiencing progression and 1 death. Neutropenia and thrombocytopenia were the most frequent adverse events, followed by hypertension. Grade 3 or 4 neutropenia was experienced by 66% of patients, with more events in the relapsed or refractory cohort. There was only 1 episode of neutropenic fever. A favorable impact on both perceived and objective cognitive performance during treatment was observed. The combination regimen of obinutuzumab, ibrutinib, and venetoclax offers time-limited treatment that results in deep remissions and is now being studied in phase III cooperative group trials.