We examined the spatial distribution pattern and meteorological drivers of dengue fever (DF) in Guangdong Province, China. Annual incidence of DF was calculated for each county between 2005 and 2011 and the geographical distribution pattern of DF was examined using Moran's I statistic and excess risk maps. A time-stratified case-crossover study was used to investigate the short-term relationship between DF and meteorological factors and the Southern Oscillation Index (SOI). High-epidemic DF areas were restricted to the Pearl River Delta region and the Han River Delta region, Moran's I of DF distribution was significant from 2005 to 2006 and from 2009 to 2011. Daily vapour pressure, mean and minimum temperatures were associated with increased DF risk. Maximum temperature and SOI were negatively associated with DF transmission. The risk of DF was non-randomly distributed in the counties in Guangdong Province. Meteorological factors could be important predictors of DF transmission.