Background: The outcome of lymph node positive (LN) cervical cancer (CC) with chemoradiation (CRT) is dismal, especially with involved para-aortic nodes (PAN). The anti-CTLA-4 immune checkpoint inhibitor ipilimumab (ipi) holds promise. We report the safety, tolerability, and efficacy in this GOG phase I study examining sequential ipi after CRT for CC. Methods: Patients (pts) with LN CC were treated with 6 weekly doses of cisplatin (40 mg/m2) and extended field radiation (RT). 2-6 weeks after RT, if there was no progression of disease, sequential ipi was given at the following dose levels: dose level 1: 3mg/kg, level 2: 10mg/kg, and an expansion cohort of 10mg/kg. The primary endpoints (endpts) were the maximum tolerated dose (MTD), and dose-limiting toxicities (DLT) of adjuvant ipi. Secondary endpt included the 1-yr disease free survival (DFS). Translational endpts included the effect of CRT on enumeration and subsets of T-cells, and CTLA4, PD-1 and ICOS expression. Results: 34 pts were enrolled, and 19 pts are evaluable for the endpts: 14 pts went off study to reasons unrelated to the study drug, 1 pt continues in her DLT evaluable period. Of the evaluable pts, all had pelvic LN, with 25% PAN. All pts completed CRT, 90% had 4 cycles of ipi, and the other 10% had 2 cycles of ipi. The ipi MTD was 10 mg/kg. There were 3 pts (16%) with acute grade 3 toxicity (lipase, ↓ANC, rash) which self-resolved. Most of the acute toxicities were grade 1-2 GI distress, rash, endocrinopathies. There were no minor or major RT quality deviations. With a median follow up of 12 months, there were no major late toxicities reported, with a 1-year DFS of 74%. There was no difference in CD4⁺- and CD8⁺- T cell levels nor CTLA-4 expression with sequential ipi. CRT itself increased ICOS and PD-1 expression. Conclusions: This study is the first to describe the safety of immunotherapy sequencing with definitive CRT in CC. Our data suggests that immunotherapy is tolerable and shows possible activity in this population with a historical dismal prognosis with standard therapy. CRT increased ICOS and PD-1 expression which was sustained with ipi, illustrative of immune modulation targets for future clinical trials and radioimmunotherapy combinations. Clinical trial information: NCT01711515