Background: High-risk locally advanced cervical cancer has a poor prognosis, and more than half of patients recur in 2 y. External beam radiotherapy (EBRT) with concurrent chemotherapy followed by brachytherapy is the standard of care for locally advanced cervical cancer. The immunostimulatory activity of the PD-1 inhibitor pembrolizumab (pembro) may be enhanced by concurrent chemoradiotherapy (CRT). After the KEYNOTE-158 study, in which pembro showed durable antitumor activity, pembro monotherapy was approved for patients with PD-L1–positive recurrent or metastatic cervical cancer who progressed during or after chemotherapy. ENGOT-cx11/KEYNOTE-A18 (NCT04221945) is a phase III, randomized, placebo-controlled study evaluating pembro with concurrent CRT for the treatment of locally advanced cervical cancer. Methods: Approximately 980 patients with high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA), locally advanced, histologically confirmed cervical cancer who have not received systemic therapy, immunotherapy, definitive surgery, or radiation will be randomized 1:1 to receive either 5 cycles of pembro 200 mg every 3 wk (Q3W) + CRT followed by 15 cycles of pembro 400 mg Q6W or 5 cycles of placebo Q3W + CRT followed by 15 cycles of placebo Q6W. The CRT regimen includes 5 cycles (with optional 6th dose) of cisplatin 40 mg/m² Q1W + EBRT followed by brachytherapy. Randomization is stratified by planned EBRT type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cancer stage at screening (stage IB2-IIB vs III-IVA), and planned total radiotherapy dose. Treatment will continue until the patient has received 20 cycles of pembro (5 cycles 200 mg Q3W, 15 cycles 400 mg Q6W) vs placebo (~2 y) or until disease progression, unacceptable toxicity, or withdrawal. Primary endpoints are PFS per RECIST v1.1 by blinded independent central review and OS. Secondary endpoints are PFS at 2 y, OS at 3 y, complete response at 12 wk, ORR, PFS and OS in PD-L1–positive patients, EORTC QLQ-C30 and QLQ-CX24, and safety. Enrollment is ongoing. Clinical trial information: NCT04221945