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Background: Climate change has increased the days of unseasonal temperature. Although many studies have examined the association between temperature and mortality, few have examined the timing of exposure where whether this association varies depending on the exposure month even at the same temperature. Therefore, we investigated monthly differences in the effects of temperature on mortality in a study comprising a wide range of weather and years, and we also investigated heterogeneity among regions.Methods: We analyzed 38,005,616 deaths from 148 cities in the U.S. from 1973 through 2006. We fit city specific Poisson regressions to examine the effect of temperature on mortality separately for each month of the year, using penalized splines. We used cluster analysis to group cities with similar weather patterns, and combined results across cities within clusters using meta-smoothing.Results: There was substantial variation in the effects of the same temperature by month. Heat effects were larger in the spring and early summer and cold effects were larger in late fall. In addition, heat effects were larger in clusters where high temperatures were less common, and vice versa for cold effects.Conclusions: The effects of a given temperature on mortality vary spatially and temporally based on how unusual it is for that time and location. This suggests changes in variability of temperature may be more important for health as climate changes than changes of mean temperature. More emphasis should be placed on warnings targeted to early heat/cold temperature for the season or month rather than focusing only on the extremes. [ABSTRACT FROM AUTHOR]