Background: Bevacizumab combined with chemotherapy has improved survival in the treatment of advanced NSCLC. This pilot trial was conducted to determine if bevacizumab could be incorporated into the standard chemotherapy/RT for locally advanced NSCLC. Methods: Pts with unresectable stage III NSCLC, PS 0-1, and adequate organ function were eligible. Pts were accrued in two strata, low and high risk (squamous histology, hemoptysis, tumor with cavitation or near a major vessel). Pts were treated with C 50mg/m² (d 1 and 8), E 50mg/m² (d 1-5) for 2 cycles concurrent with RT (64.8 Gy at 1.8 Gy/fx for 36 fxs) followed by consolidation D 75mg/m² and B 15 mg/kg for 3 cycles (Cohort 1). If safety was established then accrual would continue to Cohort 2 (B, d 15, 36, 57) and then Cohort 3 (B d 1, 22, 43). Results: 29 pts (17 Low, 12 High) were registered, all to Cohort 1. 26 pts (stage IIIB 19 pts, squamous 4 pt, adenosquamous 1 pt) were evaluable. 25 completed chemo/RT. Grade 3/4 toxicities during chemo/RT included: neutropenia 10 pts, thrombocytopenia 2, anemia 2, febrile neutropenia 3, esophagitis 2, pneumonitis 1. 21 were assessed for safety with D/B consolidation. The major adverse events during D/B consolidation were pneumonitis (Gr 3 - 2 pt) and 2 episodes of fatal hemoptysis in the high risk group resulting in closure of this stratum. The low risk stratum subsequently closed because of poor accrual. Median overall survival was 23 mos for low risk pts and 17 mos for the high risk stratum. Conclusions: In this trial, bevacizumab could not be successfully integrated into chemo-radiation for stage III NSCLC, particularly in pts considered at high risk for hemoptysis. The trial suffered from several temporary closures as mandated by CTEP when new bevacizumab-related toxicities were reported, contributing to slow accrual. In lower risk pts the data are insufficient to determine safety or efficacy. Supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102 and CA38926.