While fine mode particulate matter (PM(2.5)) forms the basis for regulating particles in the US and other countries, there is a serious paucity of large population-based studies of its acute effect on mortality. To address this issue, we examined the association between PM(2.5) and both all-cause and specific-cause mortality using over 1.3 million deaths in 27 US communities between 1997 and 2002. A two-stage approach was used. First, the association between PM(2.5) and mortality in each community was quantified using a case-crossover design. Second, meta-analysis was used to estimate a summary effect over all 27 communities. Effect modification of age and gender was examined using interaction terms in the case-crossover model, while effect modification of community-specific characteristics including geographic location, annual PM(2.5) concentration above 15 microg/m(3) and central air conditioning prevalence was examined using meta-regression. We observed a 1.21% (95% CI 0.29, 2.14%) increase in all-cause mortality, a 1.78% (95% CI 0.20, 3.36%) increase in respiratory related mortality and a 1.03% (95% CI 0.02, 2.04%) increase in stroke related mortality with a 10 microg/m(3) increase in previous day's PM(2.5). The magnitude of these associations is more than triple that recently reported for PM(10), suggesting that combustion and traffic related particles are more toxic than larger sized particles. Effect modification occurred in all-cause and specific-cause deaths with greater effects in subjects >or=75 years of age. There was suggestive evidence that women may be more susceptible to PM(2.5) effects than men, and that effects were larger in the East than in the West. Increased prevalence of central air conditioning was associated with a decreased effect of PM(2.5). Our findings describe the magnitude of the effect on all-cause and specific-cause mortality, the modifiers of this association, and suggest that PM(2.5) may pose a public health risk even at or below current ambient levels.