OBJECTIVE Dysregulation of tumour necrosis factor alpha (TNF alpha) production is thought to be important in rheumatoid arthritis. Since pentoxifylline and thalidomide inhibit endotoxin induced TNF production in vitro, these drugs were tested in an open study in rheumatoid arthritis patients to assess toxicity, the effect on TNF production, and the antiarthritic effects. METHODS 12 patients with active rheumatoid arthritis were treated with 1200 mg pentoxifylline and 100 mg thalidomide a day during 12 weeks. In addition, TNF production was assessed by ex vivo whole blood cultures stimulated with endotoxin. RESULTS Adverse events such as xerostomia, drowsiness, and constipation occurred in almost all patients, which led to discontinuation in three. The drugs halved the TNF production capacity during treatment (ANOVA, P < 0.03) whereas production capacity of interleukin (IL) 6, IL-10, and IL-12 was not affected. Of the nine patients who completed the study, five fulfilled the ACR-20% response criteria after 12 weeks of treatment. CONCLUSIONS Although pentoxifylline/thalidomide reduced the production capacity of TNF, the benefit/side effects ratio was poor due to multiple adverse effects, while clinical observation suggests limited efficacy.