Aim: We studied genetic epidemiology of primary large-joint (hip and knee) osteoarthritis (OA), in order to find disease risk factors by a candidate-gene approach. We used TNFA gene SNP rs1800629 in a case-control study in the Croatian Caucasian population. Method: We analyzed 225 hip and 205 knee OA patients (both with total joint replacements), and 554 healthy individuals, majority being blood donors. We genotyped for TNFA SNP rs1800629 (+308, C>T). Allelic and genotypic frequencies were compared between patients and controls. Results: The minor allele (T) of rs1800629 significantly conferred susceptibility only to hip OA (p < 5*10-5, OR = 1.81, CI 95% = 1.34 - 2.44). The major (C) allele was significantly associated with the protection to hip (p < 5*10-5, OR = 0.63, CI 95% = 0.41 - 0.74), but not knee OA. Patients with the homozygous genotype C/C had significantly lower risk of developing hip OA (< 3*10-4, OR = 0.53, CI 95% = 0.38 - 0.76), but had no association with knee OA. The homozygosity of the minor allele (T/T) has been significantly associated with susceptibility to only hip OA (< 2*10-2, OR = 2.56, CI 95% = 1.09 - 5.57). Conclusion. Our findings demonstrate that major and minor alleles of the rs1800629 are associated with lower or higher risk, respectively, to developing hip, but not knee OA in the Croatian population. The data suggest a difference in the etiology of hip OA from that of the knee, perhaps due to an unknown dissimilarity in vulnerability of these joints to the actions of TNFA. Alternatively, other genetic factors including long non-protein coding LOC100287329 and/or miR6832 in vicinity of rs1800629 might be involved in the observed risk.