Psoriasis has a strong genetic component in the development of the disease as indicated by familial occurrence and a high concordance rate among monozygotic twins. In genome-wide scans for psoriasis several susceptibility loci have been detected, but the disease-causing genes have not yet been identified. A recent scan, performed on psoriatic arthritis (PsA), which occurs in about 15% of the psoriasis patients showed a significant locus on chromosome 16 in a region that was already described by genome scan for psoriasis. CARD15, a major susceptibility gene for Crohn's disease (CD) on chromosome 16q, is an interesting candidate gene for psoriasis, because there is a documented clinical association of CD with psoriasis, and recently the association of CARD15 mutations with PsA was reported in Newfoundland population. We investigated the association of this variant with PsA and the overall psoriasis genotype in 59 independent patients with PsA in comparison with 361 age and sex-matched controls. In addition, a second cohort of 89 independent North American PsA patients was included. The diagnosis of psoriasis was made by a dermatologist based on standard clinical criteria. In these patients, PsA was defined as an inflammatory joint disease, negative rheumatoid factor, and lack of another causative condition for arthritis. Using case-control analysis, the G908R mutation was weakly associated with psoriasis and PsA, but due to the low frequency of this mutation statistical significance was not reached. All other variants including leu1007fsinsC and R702W did not show any association with psoriasis or PsA. In conclusion, a disease-causing role for CARD15 mutations could not be confirmed in German or American subjects with PsA.