Osteoarthritis (OA) is a frequent, destructive joint disease, with debilitating impact on a society regarding medical, social, and economic issues. Although causes of primary OA were still not fully elucidated, evidence points to complex genetic risk that varies among different population groups, including the interleukin-1 (IL-1) gene cluster. Here, we sought to determine allelic and genotypic frequencies of the IL-1β (IL1B) and the IL-1 receptor antagonist (IL1RN) genes using single nucleotide polymorphism (SNP) at -511(G>A; rs16944) and the variable number tandem repeat (VNTR) in a case-control study with 238 patients that have undergone total or partial knee replacement and 495 healthy blood donors as controls in Croatia. The alleles of the IL1B gene at -511G>A were detected by Taqman real-time polymerase chain reaction (PCR) method and IL1RN VNTR by amplifying its DNA by PCR. The genotypes 1-2/1-2 and 2-1/2-2 at IL1B G -511A-IL1RN (VNTR) showed trends for association with the occurrence of the knee OA in this population (P = 0.09; P = 0.07, respectively). Furthermore, neither the alleles nor the haplotypes were found associated with the predisposition to knee OA. Our findings suggest that knee OA might have a different genetic risk in this Caucasian population. We did not found significant association of the IL1 gene cluster (IL1B-IL1RN) with severe knee OA. However, we found that two genotypes (1-2/1-2 and 2-1/2-2) show a trend toward association with susceptibility to disease.