Caspase-8 (CASP8) is a key controller of apoptosis, and its deregulation is crucially involved in carcinogenesis. The aim of the present study was to evaluate the function of CASP8 polymorphisms in oral squamous carcinoma (OSCC) by evaluating the risk associated with three single-nucleotide polymorphisms (SNPs) in a case-control study in a Han Chinese patient population. A total of 505 individuals with clinically diagnosed OSCC and 507 healthy controls were tested for the three SNPs rs3834129, rs13016963 and rs1045485, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing analysis. After adjusting for other confounders, the genotype frequencies of CASP8 -652 6N ins/del promoter polymorphism (rs3834129). were found to be lower in patients with OSCC compared with normal subjects. No significant difference was detected in the genotype frequencies of rs13016963 between the patients and control subjects. However, the AA genotype frequency of rs1306963 was associated with OSCC as a risk factor among non-smokers and non-drinkers. For CASP8, rs1045485 was not present in any of the patients with OSCC or control subjects. These results suggest that the del allele of rs3834129 may play a protective role in the tumorigenesis of OSCC and may be useful as a genetic susceptibility marker for OSCC in the population studied.