We find that the four most recent human influenza pandemics (1918, 1957, 1968, and 2009), all of which were first identified in boreal spring or summer, were preceded by La Niña conditions in the equatorial Pacific. Changes in the phase of the El Niño-Southern Oscillation have been shown to alter the migration, stopover time, fitness, and interspecies mixing of migratory birds, and consequently, likely affect their mixing with domestic animals. We hypothesize that La Niña conditions bring divergent influenza subtypes together in some parts of the world and favor the reassortment of influenza through simultaneous multiple infection of individual hosts and the generation of novel pandemic strains. We propose approaches to test this hypothesis using influenza population genetics, virus prevalence in various host species, and avian migration patterns.