Oral aminosalicylates such as sulfasalazine and mesalamine are widely prescribed for the treatment of mild or moderately active distal ulcerative colitis. However, a critical review of the literature demonstrates that rectal 5-aminosalicylic acid (5-ASA) is the optimal therapy for this disease. Meta-analyses of published trials show that rectally delivered 5-ASA is superior to placebo and to conventional rectal corticosteroids in inducing remission of distal ulcerative colitis, whereas the combination of rectal 5-ASA with a rectal corticosteroid or oral aminosalicylate is superior to rectal 5-ASA alone. For maintaining remission of distal ulcerative colitis, rectal 5-ASA is significantly better than placebo and at least as effective as oral 5-ASA. The dosage forms available for rectal delivery include suppositories, foams, and liquid enemas, and selection among these preparations should be guided by the proximal extent of disease and patient preference. The efficacy of rectal 5-ASA is complemented by its low rate of reported adverse effects, which may reflect its reduced potential for systemic absorption. This review summarizes the evidence supporting the role of rectal 5-ASA as a first-line therapy for mild or moderately active distal ulcerative colitis, and offers guidelines for its use.