The Mekong Delta is vulnerable to changes in climate and hydrological events which alter environmental conditions, resulting in increased risk of waterborne diseases. Research exploring the association between climate factors and diarrhoea, the most frequent waterborne disease in Mekong Delta region, is sparse. This study evaluated the climate-diarrhoea association in Can Tho city, a typical Mekong Delta area in Vietnam. Climate data (temperature, relative humidity, and rainfall) were obtained from the Southern Regional Hydro-Meteorological Centre, and weekly counts of diarrhoea visits were obtained from Can Tho Preventive Medicine Centre from 2004 to 2011. Analysis of climate and health variables was carried out using spline function to adjust for seasonal and long-term trends of variables. A distributed lag model was used to investigate possible delayed effects of climate variables on diarrhoea (considering 0?4 week lag periods), then the multivariate Poisson regression was used to examine any potential association between climate factors and diarrhoea. The results indicated that the diarrhoea incidence peaked within the period August?October annually. Significant positive associations were found between increased diarrhoea and high temperature at 4 weeks prior to the date of hospital visits (IRR=1.07; 95 % CI=1.04?1.08), high relative humidity (IRR=1.13; 95 % CI= 1.12?1.15) and high (>90th percentile) cumulative rainfall (IRR=1.05; 95 % CI=1.05?1.08). The association between climate factors and diarrhoea was stronger in rural than urban areas. These findings in the context of the projected changes of climate conditions suggest that climate change will have important implications for residential health in Mekong Delta region.