BACKGROUND Gastrointestinal side effects are associated with the oral ingestion of 8-methoxsalen (8-MOP), including the liquid and crystalline formulations. OBJECTIVE The objective of this study was to determine whether the gastrointestinal symptoms associated with 8-MOP could be decreased by altering the route of administration. METHODS In an open pilot study, 8-MOP rectal suppositories were given to six patients with psoriasis vulgaris who had significant nausea or abdominal pain with the oral liquid form of the drug. RESULTS On a scale of 0 to 5, this group of patients reported a mean score of 4.4 for nausea, 0.3 for vomiting, 2.1 for abdominal pain, and 1.3 for headaches with oral 8-MOP. With the suppository form, the mean scores were 0 for nausea, 0 for vomiting, 0 for abdominal pain, and 0 for headaches. These latter values represent scores for the entire treatment period. Clinical severity scores of psoriasis improved from a mean of 6.5 (maximum possible score = 9) at the start of the trial to a mean of 1 at its conclusion. Plasma 8-MOP levels of more than 100 ng/ml were observed in all patients who received the suppositories; in only one patient were the 8-MOP plasma levels significantly higher with the oral form than with the rectal form. CONCLUSIONS Rectal suppositories of 8-MOP were associated with significantly fewer gastrointestinal side effects than the oral form of the drug; this was accomplished without compromising clinical efficacy.