Otlertuzumab is a novel humanized anti-CD37 protein therapeutic. This study evaluated the safety of otlertuzumab administered intravenously to patients with chronic lymphocytic leukemia (CLL). Otlertuzumab was administered IV weekly for up to 8 weeks followed by 4 monthly doses ranging from 0.03 to 20 mg/kg in the dose escalation phase and 10 to 30 mg/kg in the expansion phase. Responses were determined using the 1996 NCI criteria and 2008 IWCLL criteria. Fifty-seven patients were treated in the dose-escalation phase and 26 in the expansion phase. A maximum tolerated dose (MTD) was not identified. Pharmacokinetics of otlertuzumab was dose-proportional with a median terminal half-life of 8 days. Response occurred in 19 of 83 treated patients (23%) by NCI-96 criteria. All responses were partial, and occurred more commonly in patients with symptomatic untreated CLL (6/7) or 1-2 prior therapies (12/28) versus 3 or more therapies (1/48). Twenty percent (12/61) with serial CT scan assessment had a response per IWCLL criteria. The most frequent adverse events were infusion reactions, fatigue, nausea, and diarrhea, and were not dose-related. Otlertuzumab was well tolerated and modest clinical activity was observed. Otlertuzumab warrants further evaluation in combination with other agents for the treatment of CLL.