In a 6-month pilot study of 7 patients with rheumatoid arthritis, we tested a treatment involving the extracorporeal photoactivation of biologically inert methoxsalen (8-methoxypsoralen) by ultraviolet A energy to a form that covalently cross-links lymphocyte DNA; the injured cells are reinfused into the patient. Prior experimental studies had indicated that this regimen produces an immune reaction against antigens on treated T cells, and a clinical trial in patients with cutaneous T cell lymphoma had been successful. The current study patients were treated monthly, on 2 successive days (or biweekly, later on). Between 12 and 16 weeks of therapy, there appeared to be a breakpoint, after which the joint counts and joint scores of 4 of the patients began to improve. In 3 of the 4 patients, these measures eventually diminished by a mean of 71% and 80% of baseline values, respectively, and there was variable improvement in less direct indicators of clinical response. The joint counts and scores of the fourth patient improved modestly (by 33% and 59% of baselines, respectively) but he required alternative therapy, and those of the remaining 3 study patients did not improve. Mean slopes for the joint counts were significantly different from zero after the apparent breakpoint (but not before), whether one examined the 4 apparent responders (P = 0.01) or the entire group of 7 patients (P = 0.01). After completion of therapy, there was also a delay, of 2–3 months, in the clinical deterioration of those patients who had improved. There was only 1 mechanical adverse effect—a single episode of transient hypotension in 102 treatment sessions–-and no toxic effects. This preliminary study suggests that extracorporeal photochemotherapy may be effective, at least in the short term, in certain patients with rheumatoid arthritis, with less apparent toxicity than that of any of the drugs currently used for this disorder. It deserves further evaluation.