Background: Neoadjuvant ipilimumab (ipi) for stage IIIB-C melanoma may improve the clinical outcomes and provide access to pre/post ipi blood and tumor to gain insight into host effector and suppressor immune response mechanisms. Methods: Patients were treated with ipi (10 mg/kg IV q3weeks x 4doses total) bracketing definitive surgery. Tissue samples were obtained at baseline and at definitive surgery (week ≥ 6) and serum/PBMC collected at baseline, 6 weeks, then at 3, 6, 9, 12 months and/or progression. Flow cytometry was used to monitor the host effector and suppressor immune response in blood and evaluable tumor. Results: Thirty pts (21 male, 9 female), age 40-87 were enrolled (25 cutaneous primary, 1 unknown, 4 mucosal). Six had AJCC stage IIIB (N2b, N2c) and 24 IIIC (N3) melanoma. Ninety-three cycles have been delivered (median 4). Worst toxicities included grade 3 diarrhea/colitis (5 patients; 17%), hepatic enzyme elevations (2; 7%), rash (2; 7%), lipase (1; 3%), all manageable. Median follow up is 14 months: among 29 evaluable pts 15 (52%) continue disease free. Median PFS is 15.5 months, 95% CI = (8.1,-). The probability of 6 and 12 month PFS is 82.4% (95% CI=0.63, 0.92) and 53% (95% CI=0.31, 0.70) respectively. Peripherally, a significant increase in frequency of circulating T-regs (CD4+CD25hi+ Foxp3+; p=0.02 CD4+CD25hi+CD39+; p=0.001) from baseline to 6 weeks was observed. Greater increases in T-regs were associated with improved PFS (p=0.045; HR=0.54). Significant decreases in circulating MDSCs, were observed in monocytic HLA-DR+_/low/CD14+ MDSC subtype (p<0.0001). Spontaneous in vivo cross presentation was observed resulting in Th1 CD4 and CD8 antigen specific T-cell immunity (gp-100, MART-1, NY-ESO-1 peptides) with increase in frequency after ipi. Activated TIL in tumor increased after ipi (CD3+/CD4+/CD69+;p=0.06 and CD3+/CD8+/CD69+) with significant induction/potentiation of T-cell memory (CD8+/CD45RO+/TNF-α+;p=0.03). Conclusions: Neoadjuvant ipi exhibits promising clinical activity and significantly modulates the host effector and suppressor immune response. Full analysis of this completed trial and its correlates will be presented. Support: BMS, P30CA047904 and P50CA121973.