In the multicohort phase 2 KEYNOTE-158 study, pembrolizumab showed an objective response rate clinically significant in patients with advanced MSI-H/dMMR endometrial cancer who had had prior treatment (ClinicalTrials.gov, NCT02628067). The HRQoL (health-related quality of life) data for these individuals was presented. 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. All patients were treated with 200 mg of pembrolizumab every 3 weeks for 35 total cycles. The EORTC QLQ-C30 and EQ-5D-3L were given to patients at the start of treatment, at regular intervals during treatment, and 30 days after treatment had ended. All patients and those with the best overall response underwent pre-specified exploratory analyses of changes from baseline to week 9 in QLQ-C30 global health status (GHS)/QoL and EQ-5D-3L visual analog scale (VAS) score. About 84 out of 90 patients who were enrolled completed more than equal to 1 health-related quality-of-life questionnaire. The compliance rates on the QLQ-C30 and EQ-5D-3L were 90% and 94%, respectively, at baseline, and 92% and 93%, respectively, after week 9. Patients with a complete or partial response had the greatest rise in QLQ-C30 GHS/QoL from baseline to week 9, a mean increase of 6.08 points (95% CI, 0.71-11.46). (11.67 [5.33–18.00]-point increase). Scores on the EQ-5D-3L VAS rose by a mean of 9.11 (5.24-12.98) points for patients in CR/PR and by 6.00 (2.25-9.75) points for the entire sample. Further validating efficacy and safety data from KEYNOTE-158 and pembrolizumab use in this situation, pembrolizumab maintained or improved HRQoL in patients with previously treated advanced MSI-H/dMMR endometrial cancer.