OBJECTIVES: To test face, content and psychometric validity of the DSC-R, a widely-used patient reported outcome (PRO) measure of diabetes symptom distress, in line with FDA Guidance. METHODS: Face and content validity of the DSC-R was evaluated according to draft FDA guidance. Interviews with 20 US patients with Type-2 Diabetes Mellitus were conducted to assess the comprehensibility and acceptability of the English language DSC-R version. Patients were asked open-ended questions about their diabetes symptoms and symptom-bother before cognitive debriefing. Psychometric validity of the DSC-R was assessed using blinded data from 2 large scale trials of approximately 4000 patients each. RESULTS: All symptoms spontaneously reported by patients are included in the DSC-R. Upon probing, patients reported experiencing symptoms of itchy skin, increased hunger, sweats and gender-specific sexual symptoms not directly included in the DSC-R. Patients found all DSC-R questions easy to understand and answer, with the exception of “dull head” and “frequent voiding”. Both items had been inaccurately reworded when translated from Dutch to English. These have been corrected through subsequent linguistic validation. Patients generally understood the instructions and response options. Patients used various recall periods to answer the DSC-R other than the 4 weeks specified. Confirmatory factor analysis and multi-trait analysis indicated that the scoring of the DSC-R has strong construct validity and reliability. DSC-R domains discriminated among patients who differed according to body mass index (p<0.0001) and C-reactive protein levels (p<0.0001). CONCLUSION: The DSC-R items are regarded relevant and easily understood by patients. Revision of the recall period may be considered, in view of FDA Guidance. DSC-R demonstrated excellent psychometric properties when tested in two large-scale diabetes clinical trials.