Abstract: Assessing cumulative effects of the multiple environmental factors influencing mortality remains a challenging task. This study aimed to examine the associations between cumulative environmental quality and all-cause and leading cause-specific (heart disease, cancer, and stroke) mortality rates. We used the overall Environmental Quality Index (EQI) and its five domain indices (air, water, land, built, and sociodemographic) to represent environmental exposure. Associations between the EQI and mortality rates (CDC WONDER) for counties in the contiguous United States (n = 3,109) were investigated using multiple linear regression models and random intercept and random slope hierarchical models. Urbanicity, climate, and a combination of the two were used to explore the spatial patterns in the associations. We found 1 standard deviation increase in the overall EQI (worse environment) was associated with a mean 3.22% (95% CI: 2.80%, 3.64%) increase in all-cause mortality, a 0.54% (95% CI: –0.17%, 1.25%) increase in heart disease mortality, a 2.71% (95% CI: 2.21%, 3.22%) increase in cancer mortality, and a 2.25% (95% CI: 1.11%, 3.39%) increase in stroke mortality. Among the environmental domains, the associations ranged from –1.27% (95% CI: –1.70%, –0.84%) to 3.37% (95% CI: 2.90%, 3.84%) for all-cause mortality, –2.62% (95% CI: –3.52%, –1.73%) to 4.50% (95% CI: 3.73%, 5.27%) for heart disease mortality, –0.88% (95% CI: –2.12%, 0.36%) to 3.72% (95% CI: 2.38%, 5.06%) for stroke mortality, and –0.68% (95% CI: –1.19%, –0.18%) to 3.01% (95% CI: 2.46%, 3.56%) for cancer mortality. Air had the largest associations with all-cause, heart disease, and cancer mortality, whereas the sociodemographic index had the largest association with stroke mortality. Across the urbanicity gradient, no consistent trend was found. Across climate regions, the associations ranged from 2.29% (95% CI: 1.87%, 2.72%) to 5.30% (95% CI: 4.30%, 6.30%) for overall EQI, and larger associations were generally found in dry areas for both overall EQI and domain indices. These results suggest that poor environmental quality, particularly poor air quality, was associated with increased mortality and that associations vary by urbanicity and climate region. Jian Y, Messer LC, Jagai JS, Rappazzo KM, Gray CL, Grabich SC, Lobdell DT. 2017. Associations between environmental quality and mortality in the contiguous United States, 2000–2005. Environ Health Perspect 125:355–362; http://dx.doi.org/10.1289/EHP119