OBJECTIVE To replicate the association of frizzled-related protein (FRZB) non-synonymous polymorphisms with osteoarthritis (OA) susceptibility. METHODS Three groups of Spanish patients with OA were included: with total joint replacement due to primary OA in the hip (n = 310), or the knee (n = 277), or with hand OA (n = 242). Controls were more than 55 years old and did not show OA (n = 294). SNPs rs288326 (R200W) and rs7775 (R324G) were genotyped. RESULTS There were no significant differences in allele frequencies between controls and each of the three groups of OA patients. However, allele G of the R324G SNP showed a trend to be more frequent in patients with a clinical OA syndrome at multiple joints (p = 0.07), specifically in women of the total hip replacement group (8.3% in patients without other affected joints, 13.1% with one, 15.9% with two and 24.1% with more than two additional joints, p for trend = 0.008). CONCLUSIONS No direct replication of previous OA association findings was obtained but the results suggest that the R324G SNP of the FRZB gene may have an effect in OA development in multiple joints, with a specific severe involvement of the hip in women. This phenotype could reconcile previous studies that showed association either with generalised OA or with hip OA in women.