Despite advances in therapy, chronic lymphocytic leukemia remains an incurable disease and novel, effective therapies are needed. In this open-label, dose-escalation, phase I study, dacetuzumab (IgG1 humanized monoclonal antibody) was administered to 12 adults, all of whom had received several prior systemic therapies (median, 4; range, 2–11). Intrapatient dose escalation (maximum weekly doses of 3–8 mg/kg) was used to diminish first-dose-related inflammatory symptoms. No dose-limiting toxicities or dose-dependent trends in adverse events (AEs) were observed. The most common AEs (in ≥2 patients) were fatigue, headache, anorexia, conjunctivitis, hyperhidrosis, and night sweats, all of which were mild or moderate. No deaths, serious AEs, or discontinuations due to AEs occurred. Although no patient achieved an objective response, five patients demonstrated stable disease after 1 cycle of therapy, with no discernable correlation between dacetuzumab dose and outcome. This modest single-agent activity may warrant further testing of dacetuzumab in combination with other chronic lymphocytic leukemia therapies.