Evidence on the health effects of extreme temperatures and air pollution is copious. However few studies focused on their interaction. The aim of this study is to evaluate daily PM10 and ozone as potential effect modifiers of the relationship between temperature and natural mortality in 25 Italian cities. Time-series analysis was run for each city. To evaluate interaction, a tensor product between mean air temperature (lag 0⁻3) and either PM10 or ozone (both lag 0⁻5) was defined and temperature estimates were extrapolated at low, medium, and high levels of pollutants. Heat effects were estimated as percent change in mortality for increases in temperature between 75th and 99th percentiles. Results were pooled by geographical area. Differential temperature-mortality risks by air pollutants were found. For PM10, estimates ranged from 3.9% (low PM10) to 14.1% (high PM10) in the North, from 3.6% to 24.4% in the Center, and from 7.5% to 21.6% in the South. Temperature-related mortality was similarly modified by ozone in northern and central Italy, while no effect modification was observed in the South. This study underlines the synergistic effects of heat and air pollution on mortality. Considering the predicted increase in heat waves and stagnation events in the Mediterranean countries such as Italy, it is time to enclose air pollution within public health heat prevention plans.