We present here quantitative evidence for an increased role of interannual climate variability on the temporal dynamics of an infectious disease. The evidence is based on time-series analyses of the relationship between El Niño/Southern Oscillation (ENSO) and cholera prevalence in Bangladesh (formerly Bengal) during two different time periods. A strong and consistent signature of ENSO is apparent in the last two decades (1980-2001), while it is weaker and eventually uncorrelated during the first parts of the last century (1893-1920 and 1920-1940, respectively). Concomitant with these changes, the Southern Oscillation Index (SOI) undergoes shifts in its frequency spectrum. These changes include an intensification of the approximately 4-yr cycle during the recent interval as a response to the well documented Pacific basin regime shift of 1976. This change in remote ENSO modulation alone can only partially serve to substantiate the differences observed in cholera. Regional or basin-wide changes possibly linked to global warming must be invoked that seem to facilitate ENSO transmission. For the recent cholera series and during specific time intervals corresponding to local maxima in ENSO, this climate phenomenon accounts for over 70% of disease variance. This strong association is discontinuous in time and can only be captured with a technique designed to isolate transient couplings.