Hand-foot-and-mouth disease (HFMD) is becoming one of the common airborne and contact transmission diseases in Guangzhou, southern China, leading public health authorities to be concerned about its increased incidence. In this study, we aimed to examine the effect of weather patterns on the incidence of HFMD in the subtropical city of Guangzhou for the period 2009-2012, and assist public health prevention and control measures. A negative binomial multivariable regression was used to identify the relationship between meteorological variables and HFMD. During the study period, a total of 166,770 HFMD-confirmed cases were reported, of which 11 died, yielding a fatality rate of 0·66/10,000. Annual incidence rates from 2009 to 2012 were 132·44, 311·40, 402·76, and 468·59/100,000 respectively. Each 1°C rise in temperature corresponded to an increase of 9·38% (95% CI 8·17-10·51) in the weekly number of HFMD cases, while a 1 hPa rise in atmospheric pressure corresponded to a decrease in the number of cases by 6·80% (95% CI -6·99 to -6·65), having an opposite effect. Similarly, a 1% rise in relative humidity corresponded to an increase of 0·67% or 0·51%, a 1 m/h rise in wind velocity corresponded to an increase of 4·01% or 2·65%, and a 1 day addition in the number of windy days corresponded to an increase of 24·73% or 25·87%, in the weekly number of HFMD cases, depending on the variables considered in the model. Our findings revealed that the epidemic status of HFMD in Guangzhou is characterized by high morbidity but low fatality. Weather factors had a significant influence on occurrence and transmission of HFMD.