The classic risk factors for developing coronary heart disease (CHD) explain less than 50% of the decrease in mortality observed since 1950. The transition currently under way, from the degenerative to the infectious-inflammatory paradigm, requires a new causal interpretation of temporal trends. The following is an ecological study based on data from the United States showing that in men and women an association between the age distribution of mortality due to influenza and pneumonia (I&P) associated with the influenza pandemic in 1918-1919 in the 10-49-year age bracket and the distribution of CHD mortality from 1920 to 1985 in survivors from the corresponding birth cohorts. It further shows a significant negative correlation (r = -0.68, p = 0.042) between excess mortality from I&P accumulated in epidemics from 1931 to 1940 (used as indicator for persistent circulation of H1N1 virus combined with vulnerability to infection) and the order of the beginning in the decline in CHD mortality in nine geographic divisions in the United States. In light of current biological knowledge, the data suggest that the 1918 influenza pandemic and the subsequent epidemics up to 1957 might have played a determinant role in the epidemic of CHD mortality registered in the 20th century.