BACKGROUND: Extreme hot weather conditions have been associated with increased morbidity and mortality, but risks are not evenly distributed throughout the population. Previously, a heat vulnerability index (HVI) was created to geographically locate populations with increased vulnerability to heat in metropolitan areas throughout the United States. OBJECTIVES: We sought to determine whether areas with higher heat vulnerability, as characterized by the HVI, experienced higher rates of morbidity and mortality on abnormally hot days. METHODS: We used Poisson regression to model the interaction of HVI and deviant days (days whose deviation of maximum temperature from the 30-year normal maximum temperature is at or above the 95th percentile) on hospitalization and mortality counts in five states participating in the Environmental Public Health Tracking Network for the years 2000 through 2007. RESULTS: The HVI was associated with higher hospitalization and mortality rates in all states on both normal days and deviant days. However, associations were significantly stronger (interaction p-value < 0.05) on deviant days for heat-related illness, acute renal failure, electrolyte imbalance, and nephritis in California, heat-related illness in Washington, all-cause mortality in New Mexico, and respiratory hospitalizations in Massachusetts. CONCLUSION: Our results suggest that the HVI may be a marker of health vulnerability in general, although it may indicate greater vulnerability to heat in some cases.