Based on autopsy data collected in Southern China from 2001-2006, 975 cases of sudden unexplained nocturnal death syndrome (SUNDS) were surveyed. Genetic screening of SCN5A gene encoding the voltage dependent cardiac sodium channel was performed in 74 SUNDS cases. The annual occurrence rate of SUNDS in the area was estimated to be about 1 per 100,000 people. About 80.6% of deaths occurred between the ages of 21 to 40 years and the case number peaked at age 30 years. In 75.4% of cases with witnesses, victims died asleep between 11 PM and 4 AM and they showed predominantly abrupt respiratory distress shortly preceding death. The monthly distribution of emergency fever cases in the area during the same period was positively correlated to that of SUNDS cases (r(s) = 0.611, P = 0.035). Four polymorphisms in SCN5A were identified in both SUNDS and control groups. Compared with controls, the allele frequency of C5457 and C3666 + 69 were significant higher in SUNDS (P < 0.005) while the genotypes of both 5457CC (P = 0.012, OR = 2.0, 95% CI = 1.3-3.2) and 3666+69CC (P = 0.004, OR = 2.1, 95% CI = 1.3-3.3) in SUNDS cases were significantly higher. This is the first report of an epidemiological survey and SCN5A gene screening in SUNDS in the Han population of China. The genotypes of 5457CC and 3666+69CC in SCN5A gene may be Chinese SUNDS susceptible polymorphisms.