OBJECTIVES: This study aimed to determine the validity (construct, known-groups), reliability (internal consistency), and floor and ceiling effects of the 12 item Medical Outcomes Study Short-Form Health Survey version 2 (SF-12v2) among adults with autism. METHODS: Study data was collected using an online survey (Qualtrics software system) of 291 adults with autism registered with the Interactive Autism Network (IAN).  Using confirmatory factor analysis, construct validity of the SF-12v2 was examined by comparing model fits across four different iterations of the SF-12v2 two-factor structure.  Known-groups validity was assessed by comparing SF-12v2 physical component summary (PCS) and mental component summary (MCS) score by autism severity.  Internal consistency reliability was determined using Cronbach’s alpha.  Floor and ceiling effects were assessed based on the percentage of participants scoring the lowest and highest possible score, respectively.    RESULTS: Results from CFA indicated an adequate fit with the data for the two-factor SF-12v2 model with minor modifications.  As per known-groups validity, the SF-12v2 MCS domain adequately distinguished adults with autism by severity, with higher MCS score observed among adults with low autism severity as compared to those with high autism severity.  However, contrary results were observed for the PCS domain.  High internal consistency reliability was observed for the PCS domain (Cronbach’s alpha 0.87), MCS domain (Cronbach’s alpha 0.73), and overall instrument (Cronbach’s alpha 0.84).  There were no floor and ceiling effects. CONCLUSIONS: The SF-12v2 had good construct validity, and the factor structure fit well with the data.  The known-groups validity of the SF-12v2 warrants further investigation in this population.  Reliability of the instrument was good, and there were no floor and ceiling effects.  Overall, SF-12v2 had adequate psychometric properties among adults with autism.