In the phase 2 multi-cohort KEYNOTE-158 study, pembrolizumab showed an objective response rate that was clinically significant in patients with advanced MSI-H/dMMR endometrial cancer who had had prior treatment. Researchers report on the patient’s health-related quality of life (HRQoL). Patients with advanced MSI-H/dMMR endometrial cancer who were part of cohorts D (endometrial cancer, any MSI status) and K (any MSI-H/dMMR solid tumor except colorectal) were included in this analysis. Patients were administered 200 mg of pembrolizumab every 3 weeks for 35 total cycles. At baseline, periodically during therapy, and 30 days following treatment discontinuation, the EORTC QLQ-C30, and EQ-5D-3L questionnaires were given. Changes in global health status (GHS)/quality of life (QoL) on the QLQ-C30 from baseline to week 9 and in the EQ-5D-3L visual analog scale (VAS) score were among the pre-specified exploratory analyses performed for all patients, and by greatest overall response. Around 84 out of 90 patients who were enrolled completed more than or equal to 1 health-related quality-of-life questionnaire. Compliance rates on the QLQ-C30 and EQ-5D-3L were 90% and 94% at baseline and 92% and 93% after week 9. Total population QLQ-C30 GHS/QoL improved by 6.08 (0.71-11.46) points from baseline to week 9, with a larger improvement in patients who obtained complete or partial response (11.67 [5.33–18.00]-point increase). The mean (95% CI) change in EQ-5D-3L VAS scores was 6.00 (2.25-9.75) for the entire sample and 9.11 (5.24-12.98) for patients in CR/PR. In patients with advanced MSI-H/dMMR endometrial cancer who had previously been treated, pembrolizumab maintained or improved HRQoL, lending more support to the effectiveness and safety results from KEYNOTE-158 and pembrolizumab use in this scenario.