Mismatch repair protein-deficient non-neoplastic colonic crypts and endometrial glands (dMMR crypts and glands) have been reported as a unique marker of underlying Lynch syndrome (LS). However, no large studies have directly compared the frequency of detection in cases with double somatic (DS) MMR mutations. We retrospectively analyzed 42 colonic resection specimens (24 LS, 18 DS) and 20 endometrial specimens (9 LS, 11 DS) including 19 hysterectomies and 1 biopsy for dMMR crypts and glands. All specimens were from patients with known primary cancers including colonic adenocarcinomas and endometrial endometrioid carcinomas (including two mixed carcinomas). Four blocks of normal mucosa away from tumor were selected from most cases, as available. MMR immunohistochemistry (IHC) specific to the primary tumor mutations were analyzed. dMMR crypts were found in 65% of LS and 0% of DS MMR mutated colonic adenocarcinomas (p < 0.001). Most dMMR crypts were detected in the colon (12 of 15) compared to ileum (3). dMMR crypts showed single and grouped loss of MMR IHC expression. dMMR glands were found in 67% of LS and 9% (1 of 11) of DS endometrial cases (p = 0.017). Most dMMR glands were found in the uterine wall, with 1 LS and 1 DS case exhibiting dMMR glands in the lower uterine segment. The majority of cases exhibited multifocal and grouped dMMR glands. No morphologic atypia was identified in dMMR crypts or glands. Overall, we demonstrate that dMMR crypts and glands are highly associated with underlying LS, while rarer in those with DS MMR mutations.