Despite the widespread use of methotrexate in the treatment of psoriatic arthritis (PsA), there are patients who are either refractory, develop toxicity to, or refuse to take methotrexate. In search of an alternative, we studied long-term tolerability of and clinical response to azathioprine (AZA) in PsA patients in comparison with matched controls and followed them in a longitudinal clinic. Twenty-eight of 485 patients followed prospectively between 1978 and 1998 took AZA during their clinic follow-ups. Eighteen of the 28 took AZA for 12 months and were included in the study. AZA was well tolerated by most patients, even in the long-term. Although there was no statistically significant difference in the reduction in number of actively inflamed joints between AZA-treated patients and controls, and AZA was no better in preventing progression of damage, AZA was still as good as the other medications. Consequently, AZA was often given to individuals who had not responded to other medications in the past. We provide illustrative case reports in which AZA also controlled psoriasis, and we conclude that, whereas AZA is not superior to other medications in the treatment of PsA, it may be safely used and it provides an alternative therapy for patients with PsA.