Hand, foot and mouth disease (HFMD) was an emerging viral infectious disease in recent years in Shenzhen. The underlying risk factors have not yet been systematically examined. This study analyzed the short-term effect of El Niño-Southern Oscillation on pediatric HFMD in Shenzhen, China. Daily count of HFMD among children aged below 15 years old, Southern Oscillation Index (SOI), and weather variables were collected to construct the time series. A distributed lag non-linear model was applied to investigate the effect of daily SOI on pediatric HFMD occurrence during 2008-2010. We observed an acute effect of SOI variation on HFMD occurrence. The extremely high SOI (SOI = 45, with 0 as reference) was associated with increased HFMD, with the relative risk (RR) being 1.66 (95% Confidence Interval [CI]: 1.34-2.04). Further analyses of the association between HFMD and daily mean temperature and relative humidity supported the correlation between pediatric HFMD and SOI. Meteorological factors might be important predictors of pediatric HFMD occurrence in Shenzhen.