Hand, foot and mouth disease (HFMD) is a contagious viral illness that commonly affects infants and children. The underlying risk factors have not yet been systematically examined. This study analyzed the short-term effects of meteorological factors on children HFMD in Guangzhou, China. Daily count of HFMD among children younger than 15 years and meteorological variables from 2009 to 2011 were collected to construct the time series. A generalized additive model was applied to estimate the effects of meteorological factors on HFMD occurrence, after adjusting for long-term trend, seasonal trend, day of week, and public holidays. A negative association between temperature and children HFMD occurrence was observed at lag days 1-3, with the relative risk (RR) for a 1 °C increase on lag day 2 being 0.983 (95% confidence intervals (CI) 0.977 to 0.989); positive effect was found for temperature at lag days 5-9, with the highest effect at lag day 6 (RR = 1.014, 95% CI 1.006 to 1.023). Higher humidity was associated with increased HFMD at lag days 3-10, with the highest effect at lag day 8 (RR = 1.009 for 1% increase in relative humidity, 95% CI 1.007 to 1.010). And we also observed significant positive effect for rainfall at lag days 4 and 8 (RR = 1.001, 95% CI 1.000 to 1.002) for 1-mm increase. Subgroup analyses showed that the positive effects of temperature were more pronounced among younger children. This study suggests that meteorological factors might be important predictors of children HFMD occurrence in Guangzhou.