The purpose of this study was to determine health-related quality of life (HRQOL) among adults with autism, and compare it to the HRQOL of the general adult population in the United States (US). Factors predicting HRQOL of adults with autism were also identified. A cross-sectional online survey was conducted to gather study information. From adults with autism registered with the Interactive Autism Network (IAN), those aged 18 years and above and having the capacity to self-report were identified and approached for study participation. The final sample included 291 adults with autism. One-way t-test revealed adults with autism to have significantly lower physical and mental HRQOL than their counterparts in the US population. Using linear regression analysis, modifiable factors including social support and coping along with other socio-demographic and medial characteristics were identified as significant predictors of physical and mental HRQOL. Greater perceived adequacy of social support from friends and family was associated with better HRQOL, while greater use of maladaptive coping was associated with lower HRQOL. Clinicians and other health interventionist should consider assessing these factors among adults with autism, and provide necessary capabilities to these adults with the aim of improving their HRQOL.