In this study we characterized the relationship between temperature and mortality in central Arizona desert cities that have an extremely hot climate. Relationships between daily maximum apparent temperature (AT[subscript max]) and mortality for eight condition-specific causes and all-cause deaths were modeled for all residents and separately for males and females ages <65 and ≥65 during the months May–October for years 2000–2008. The most robust relationship was between ATmax on day of death and mortality from direct exposure to high environmental heat. For this condition-specific cause of death, the heat thresholds in all gender and age groups (AT[subscript max] = 90–97 °F; 32.2‒36.1 °C) were below local median seasonal temperatures in the study period (AT[subscript max] = 99.5 °F; 37.5 °C). Heat threshold was defined as AT[subscript max] at which the mortality ratio begins an exponential upward trend. Thresholds were identified in younger and older females for cardiac disease/stroke mortality (AT[subscript max] = 106 and 108 °F; 41.1 and 42.2 °C) with a one-day lag. Thresholds were also identified for mortality from respiratory diseases in older people (AT[subscript max] = 109 °F; 42.8 °C) and for all-cause mortality in females (AT[subscript max] = 107 °F; 41.7 °C) and males <65 years (AT[subscript max] = 102 °F; 38.9 °C). Heat-related mortality in a region that has already made some adaptations to predictable periods of extremely high temperatures suggests that more extensive and targeted heat-adaptation plans for climate change are needed in cities worldwide.