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Background: Microsatellite instability–high (MSI‐H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter responses to ICIs is unclear. This article reports data from a prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI‐H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential mechanisms of primary/secondary ICI resistance (NCT02899793). Methods: Patients with measurable MSI‐H/dMMR EC confirmed by polymerase chain reaction/immunohistochemistry were evaluated by WES and received 200 mg of pembrolizumab every 3 weeks for ≤2 years. The primary end point was the objective response rate (ORR). Secondary end points included progression‐free survival (PFS) and overall survival (OS). Results: Twenty‐five patients (24 evaluable) were treated. Six patients (25%) harbored Lynch/Lynch‐like tumors, whereas 18 (75%) had sporadic EC. The tumor mutation burden was higher in Lynch‐like tumors (median, 2939 mutations/megabase [Mut/Mb]; interquartile range [IQR], 867‐5108 Mut/Mb) than sporadic tumors (median, 604 Mut/Mb; IQR, 411‐798 Mut/Mb; P =.0076). The ORR was 100% in Lynch/Lynch‐like patients but only 44% in sporadic patients (P =.024). The 3‐year PFS and OS proportions were 100% versus 30% (P =.017) and 100% versus 43% (P =.043), respectively. Conclusions: This study suggests prognostic significance of Lynch‐like cancers versus sporadic MSI‐H/dMMR ECs for ORR, PFS, and OS when patients are treated with pembrolizumab. Larger confirmatory studies in ECs and other MSI‐H/dMMR tumors are necessary. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI‐H ECs. Oligoprogression in MSI‐H/dMMR patients appears salvageable with surgical resection and/or local treatment and the continuation of pembrolizumab off study. Clinical studies evaluating separate MSI‐H/dMMR EC subtypes treated with ICIs are warranted. This study suggests prognostic significance of Lynch‐like cancers versus sporadic microsatellite instability–high (MSI‐H) endometrial cancers (ECs) for the objective response rate, progression‐free survival, and overall survival when patients are treated with pembrolizumab. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI‐H ECs, and clinical studies evaluating separate MSI‐H EC subtypes treated with immune checkpoint inhibitors are warranted. [ABSTRACT FROM AUTHOR]