Background: Venetoclax is a potent, selective, oral BCL-2 inhibitor that has activity in patients (pts) with relapsed/refractory (R/R) CLL, with an objective response rate of > 70%. Here we report the aggregated venetoclax monotherapy safety analysis from 3 pooled trials in R/R CLL. Methods: An integrated safety analysis was conducted for pts with R/R CLL who received venetoclax monotherapy in a phase 1 dose escalation and two phase 2 trials (N = 328). Pts who received the recommended phase 2 dose of 400 mg once daily (QD) were analyzed for incidence and timing of adverse events (AEs) and are reported here. Results: Pts receiving 400 mg QD (n = 279) included 181 pts with del 17p and 75 pts with previous B cell receptor inhibitor failure. As of Aug 25, 2015, the median duration on treatment was 10.3 months and 65.6% of pts were still on study. Discontinuation occurred in 96 pts, with 24 pts discontinuing due to adverse events (AEs). The most common ( > 20% pts) AEs of any grade (Gr) were neutropenia (38%), diarrhea (38%), nausea (36%), anemia (26%), fatigue (24%), and upper respiratory tract infection (21%). The most common ( > 10% pts) Gr 3/4 AEs were neutropenia (36%), anemia (15%), and thrombocytopenia (13%). Cytopenias occurred early and rates decreased over time. Serious AEs ( > 2% pts) were pneumonia (5%), febrile neutropenia (5%), pyrexia (3%), and autoimmune hemolytic anemia (3%). There were 41 deaths, 11 due to AEs not associated with disease progression. Under the most recent tumor lysis syndrome (TLS) mitigation guidelines, which align prophylactic measures with the pt’s relative risk, 4/105 pts (4%) experienced laboratory TLS, all Gr 3. All TLS events were observed within the initial 5-wk dose ramp-up and were managed with hydration, electrolyte correction, and dose interruption. All pts were able to resume dosing without clinical sequelae. Conclusions: Venetoclax 400 mg QD has an established and manageable safety profile for the treatment of R/R CLL pts, including those who may not be appropriate candidates for other approved treatments. Clinical trial information: NCT01328626; NCT01889186; NCT02141282