Background: The anti-apoptotic protein Bcl-2 is a highly expressed in NHL and contributes to chemotherapy resistance. ABT-199 is a selective, orally bioavailable, small molecule Bcl-2 inhibitor that is a promising agent for the treatment of patients (pts) with NHL. Methods: Objectives of this Phase I, dose-escalation study include evaluations of safety, pharmacokinetics (PK), and preliminary efficacy in pts with R/R NHL. ABT-199 was given on Week 1 Day -7 (W1D-7), followed by continuous, once-daily dosing from W1D1 until progressive disease or unacceptable toxicity. A 2 to 3 week lead-in period with stepwise dose titration was implemented. Final cohort doses of 200 - 900 mg have been evaluated. Results: As of December 4, 2013, 44 pts have been enrolled, 15 (35%) with mantle cell lymphoma (MCL), 11 (26%) with FL, 10 (23%) with DLBCL, 4 (9%) with Waldenström macroglobulinemia (WM), 2 (5%) with marginal zone (MZL), 1 (2%) with primary mediastinal B-cell lymphoma (PMBCL), and 1 (2%) with multiple myeloma (MM). The most common AEs (≥20% of pts) were nausea (34%), upper respiratory tract infection (27%), diarrhea (25%), and fatigue (21%). Grade (G) 3/4 AEs occurring in >3 pts were anemia (14%), neutropenia (11%), and thrombocytopenia (9%). G 3/4 thrombocytopenia was not dose-dependent or dose-limiting. Two of 10 pts in cohort 5 experienced a DLT (G3 febrile neutropenia and G4 neutropenia) at the target dose of 600 mg. G3 laboratory tumor lysis syndrome was seen after the initial dose in 1 pt with bulky MCL (elevations in phosphate and potassium only) and 1 pt with DLBCL (elevations in phosphate and uric acid only). For the 40 pts evaluable for efficacy, the overall response rate was 48%, 9/12 MCL (1 CR); 3/11 FL; 3/9 DLBCL (1 CR); 3/4 WM (1 CR); 1/2 MZL; 0/1 PMBCL; 0/1 MM. All responses in DLBCL and FL pts were observed at doses ≥600 mg; 3/8 DLBCL (38%) and 3/6 FL (50%). Conclusions: ABT-199 monotherapy showed anti-tumor activity across the range of ABT-199 cohort doses for several NHL subtypes, most notably in MCL and WM. In DLBCL and FL, responses were observed at higher doses. Dose escalation is continuing to determine the MTD and RP2D. Clinical trial information: NCT01328626.