Reiter's syndrome is one of the reactive forms of seronegative spondyloarthropathies. Various therapies used in the management of Reiter's syndrome are nonsteroidal antiinflammatory drugs (NSAIDs), antibiotics, and disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine (SSZ) or methotrexate (MTX). There is only one case report of successful treatment of Reiter's syndrome with tumor necrosis factor-alpha (TNF-alpha) blockers in human immunodeficiency virus (HIV) patient (Gaylis N, 2003, J Rheumatol 30(2):407-411 Feb). We hereby report a case of Reiter's syndrome treated successfully with infliximab, an anti-TNF-alpha chimeric monoclonal antibody. A 28-year-old white male presented with painful swelling of right elbow and ankle joints, urethritis. and lesions involving skin of soles of feet and penis. Detailed work-up of sexually transmitted diseases (STDs), HIV, and systemic etiology were negative. Despite aggressive treatment with antibiotics, NSAIDS, prednisone, and MTX for 3 months, he had persistent synovitis and worsening of skin lesions. He was then treated with infliximab 200 mg intravenously at weeks 0, 2, 6, and 14 weeks which resulted in complete resolution of arthritis and skin lesions within 6 weeks of infliximab therapy.