BACKGROUND: Air conditioning has been proposed as one of the key factors explaining reductions of heat-related mortality risks observed in the last decades. However, direct evidence is still limited. METHODS: We used a multi-country, multi-city, longitudinal design to quantify the independent role of air conditioning in reported attenuation in risk. We collected daily time series of mortality, mean temperature, and yearly air conditioning prevalence for 311 locations in Canada, Japan, Spain, and the USA between 1972 and 2009. For each city and sub-period, we fitted a quasi-Poisson regression combined with distributed lag non-linear models to estimate summer-only temperature-mortality associations. At the second stage, we used a novel multilevel, multivariate spatio-temporal meta-regression model to evaluate effect modification of air conditioning on heat-mortality associations. We computed relative risks and fractions of heat-attributable excess deaths under observed and fixed air conditioning prevalences. RESULTS: Results show an independent association between increased air conditioning prevalence and lower heat-related mortality risk. Excess deaths due to heat decreased during the study periods from 1.40% to 0.80% in Canada, 3.57% to 1.10% in Japan, 3.54% to 2.78% in Spain, and 1.70% to 0.53% in the USA. However, increased air conditioning explains only part of the observed attenuation, corresponding to 16.7% in Canada, 20.0% in Japan, 14.3% in Spain, and 16.7% in the USA. CONCLUSIONS: Our findings are consistent with the hypothesis that air conditioning represents an effective heat adaptation strategy, but suggests that other factors have played an equal or more important role in increasing the resilience of populations.