OBJECTIVES:  This study examined the psychometric properties of version 2 of the SF-12 Health Survey (SF-12v2) among adults with hemophilia in the United States. METHODS: A cross-sectional design using web-based and paper-based self-administered surveys was utilized. Patients were recruited using an online panel, a Facebook community of hemophilia patients, and a hemophilia treatment clinic. The psychometric properties of the SF-12v2 were assessed for construct validity, internal consistency reliability, and presence of floor and ceiling effects. RESULTS: A total of 218 respondents completed the survey, with most recruited via the online panel (n = 197). Confirmatory factor analysis using the WLSMV estimator in Mplus supported a two-factor model for the SF-12v2 where the physical functioning, role physical, bodily pain, and general health items loaded onto a latent physical factor (LPF) while the role emotional, mental health, social functioning, and vitality items loaded onto a latent mental factor (LMF). Correlated residuals for items belonging to similar domains were estimated and there was a significant correlation between LPF and LMF. All standardized factor loadings were strong and statistically significant, indicating adequate convergent validity. Item-to-other scale correlations were lower than item-to-hypothesized scale correlations and model testing revealed that LPF and LMF were not perfectly correlated, suggesting good item and construct discriminant validity. Significant decreases in physical component summary (PCS) and mental component summary (MCS) scores were associated with increasing symptom severity, supporting known-groups validity. Internal consistency reliability was satisfactory, with Cronbach’s alpha of 0.848 for the LPF and 0.785 for the LMF items. None of the participants received the least or maximum possible PCS or MCS score, indicating the absence of floor and ceiling effects. CONCLUSIONS:  Overall, the SF-12v2 was found to be psychometrically valid. These results provide a basis for its use in future studies designed to measure the health-related quality of life of adults with hemophilia.