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Objectives: Testing for NRAS mutation at codon Q61 is of therapeutic, prognostic, and diagnostic importance for metastatic melanoma, thyroid carcinoma, and colorectal carcinoma. Immunohistochemistry for NRASQ61R, the most common NRAS mutation, offers several practical advantages over current molecular diagnostic techniques.Methods: We investigated the sensitivity and specificity of NRASQ61R in a series of 149 tumors with known NRAS genotype (72 malignant melanomas, 13 melanocytic nevi, 28 thyroid carcinomas, 25 gastrointestinal carcinomas, and 11 other malignancies).Results: Thirty-five cases harbored the NRASQ61R mutation (19 malignant melanomas, one melanocytic nevus, 10 thyroid carcinomas, two gastrointestinal carcinomas, and three other malignancies). In this series, the concordance rate between immunohistochemistry and mutational analyses was 100%. The sensitivity and specificity were 100% and 100%, respectively. However, lower staining intensity was observed for thyroid carcinomas in comparison to melanomas and other tumors.Conclusions: Our studies confirmed that immunohistochemistry provides excellent sensitivity and specificity for detecting the NRASQ61R mutation in a variety of tumor types in a clinical setting.