Background: Tobacco-related non-small cell lung cancer (NSCLC) is associated with reduced survival and greater genomic instability. Veliparib (V) is a PARP inhibitor that augments platinum-induced DNA damage in preclinical studies, and a recent Ph 2 trial of advanced NSCLC trended to improved survival (HR 0.80; CI 0.54–1.18) when V was added to carboplatin (C) and paclitaxel (P). Here we report outcomes based on smoking status from a randomized Ph 2 study of CP with either V or placebo in advanced NSCLC. Methods: Patients (pts) with previously untreated advanced/metastatic NSCLC were randomized 2:1 to CP with either V at 120 mg BID or placebo (pre-specified stratification by histology and smoking history). Cotinine (COT) was measured in pt plasma samples as an index of recent tobacco use. Results: Of 158 pts, 68% were male, and 49% had squamous NSCLC. At study entry, 60% of pts were self-reported current smokers (CS), 27% former smokers, and 13% never smoked. There were no significant differences in V PK parameters between the COT-high and low pts.Most common AE in CS were neutropenia (41% VCP; 27% CP), alopecia (36%; 33%), and anemia (31%; 40%). G3/4 AEs were elevated in CS treated with VCP vs CP (66% vs. 40%, p=0.026); all-grade AEs and SAEs were similar between the two groups. In a COT sensitivity analysis of OS, HR VCP/CP for COT-high was 0.52 (0.29–0.92) and COT-low was 1.07 (0.63–1.81). Conclusions: Smoking status was a strong predictor of efficacy for veliparib-chemotherapy combination in advanced NSCLC. No differences in PK of V were seen based on plasma COT; toxicity of VCP was acceptable regardless of smoking history. A Ph 3 study has been initiated in pts with smoking history. Clinical trial information: NCT01560104