Osteoarthritis (OA) is a multifactorial disorder in which genetic factors act as important contributors to its onset and progression. Associations between genetic polymorphisms of the interleukin-1 (IL-1) gene cluster and OA susceptibility have been studied continuously in different ethnic groups, yielding controversial results. This study investigated the association of interleukin-1beta (-511C/T) and interleukin-1 receptor antagonist (86-bp VNTR) polymorphisms with knee OA susceptibility in a Chinese Han population. A case-control association study was conducted. The two polymorphisms were genotyped in 453 patients who had primary symptomatic knee OA with radiographic confirmation and in 487 matched controls. Allelic and genotypic frequencies and haplotype distribution were compared between OA and control subjects. For either of the two loci, no significant difference was detected in genotype or allele distribution between knee OA and control groups (all P > 0.05). The haplotype distribution of the two loci showed no difference between the two groups, either. Furthermore, no association between the genotype of the -511 and VNTR polymorphisms and the clinical variables, age, sex, body mass index and Kellgren/Lawrence score was observed in OA patients. The genetic polymorphisms of interleukin-1beta and interleukin-1 receptor antagonist are not risk factors for OA etiology in Han Chinese.