Case report data and a matched case-control study were used to investigate the epidemiological characteristics of hand, foot and mouth disease (HFMD) in children in Shenzhen, China between 2008 and 2011. Multivariate analyses were used to evaluate factors associated with severity of infection. Laboratory tests were performed to determine aetiological identification for samples from 163 severe and fatal cases as well as an outpatient-based HFMD sentinel surveillance system (n = 446). All identified EV71 belonged to sub-genotype C4a. No major changes in the CA16 and EV71 viruses were found until the end of 2011. Annual attack rates and the case-severity ratios (CSRs) rose from 0·82/1000 and 0·56/1000, respectively, in 2008 to 2·12/1000 and 6·13/1000 in 2011. The CSR was higher in migrants than in local residents. The adjusted odds ratio (OR) of having a severe attack for being a migrant was 2·45, having a fever >39°C (OR 5·77), visiting a private clinic (OR 2·65), longer time from symptom onset to diagnosis (OR 1·49), visiting a doctor (OR 1·51), early use of intramuscular pyrazolone (OR 3·36), early use of intravenous glucocorticoids (OR 2·28), or the combination of both (OR 3·75). The mortality and increasing case severity appears to be associated with socioeconomic factors including migration and is of worldwide concern.