Background: Cervical cancer arises in the setting of persistent infection with high-risk human papillomavirus subtypes. Many patients with early-stage and locally advanced carcinoma can be salvaged with radical surgery and chemoradiation, respectively. However, women with recurrent/metastatic disease represent a poor prognostic group with high unmet clinical needs. Incorporation of anti-angiogenesis therapy has emerged as a therapeutic option, but the survival benefit of 3.7 months over chemotherapy (CT) alone is modest (Tewari et al. NEJM 2014). Because viral tumor antigen-specific T cells reside predominantly in programmed cell death 1–expressing T-cell compartments, checkpoint inhibition may unleash a diverse antitumor T-cell response. Based on the 14.3% objective response in KEYNOTE-158, the US FDA granted accelerated approval to pembrolizumab (pembro) in June 2018 for second-line therapy and beyond. Methods: KEYNOTE-826 is a phase 3, randomized, double-blind, placebo-controlled, multinational trial of CT with pembro or with placebo for first-line treatment of recurrent, persistent, or metastatic cervical cancer. Patients not previously treated with CT for recurrence who are not amenable to curative treatment will be randomized 1:1 to CT + pembro 200 mg or placebo every 3 weeks. The CT regimen (paclitaxel 175 mg/m² + cisplatin 50 mg/m² or carboplatin AUC 5, with or without bevacizumab 15 mg/kg) will be selected by the investigator before randomization. Stratification factors include metastasis status at diagnosis, bevacizumab use (yes/no), and tumor PD-L1 status (combined positive score <1, 1 to <10, or ≥10). Treatment will continue until disease progression, unacceptable toxicity, or voluntary patient withdrawal for up to 35 cycles (~2 years). Primary endpoints are progression-free survival (PFS) per RECIST v1.1 assessed by blinded independent central review and overall survival. Secondary endpoints are objective response, duration of response, 12-month PFS, patient-reported quality of life, and safety. Enrollment is ongoing. Clinical trial information: NCT03635567