The factors having the greatest impact on self-reported health status in adults with congenital heart disease (ACHD) remain incompletely studied. We conducted a single-site, cross-sectional study of ACHD patients followed at the Center for ACHD at Washington University School of Medicine, including retrospectively gathered clinical data and psychometric and health status assessments completed at the time of enrollment. To identify primary drivers of perceived health status, we investigated the impact of the demographic, clinical, and psychological variables on self-reported health status as assessed using the Rand 36-Item Short Form Health Survey. Variables with significant associations within each domain were considered jointly in multivariable models constructed via stepwise selection. There was domain-specific heterogeneity in the variables having the greatest effect on self-reported health status. Depression was responsible for the greatest amount of variability in health status in all domains except physical functioning. In the physical functioning domain, depression remained responsible for 5% of total variability, the third most significant variable in the model. In every domain, depression more strongly influenced health status than did any cardiac-specific variable. In conclusion, depression was responsible for a significant amount of heterogeneity in all domains of self-perceived health status. Psychological variables were better predictors of health status than clinical variables.