We assessed the efficacy and side effects of oral enprofylline in the maintenance therapy of 206 asthmatics 19 to 71 yr of age. After a 1-wk placebo run-in, patients were randomized to receive in double-blind fashion one of three doses of slow-release enprofylline tablets (150 mg, 300 mg, or 450 mg twice daily) or matching placebo for 4 wk. At baseline, mean (SD) peak expiratory flow rate (PEFR) was 62 (19)% of predicted normal values. The mean increase in morning PEFR 12 h after dosing was: for 450 mg, 14(17)%; for 300 mg, 8(23)%; for 150 mg, 2(11)%, for placebo 0(10)%. The increases over baseline for 450 mg and 300 mg compared with 150 mg and placebo were statistically significant. The mean asthma symptoms score (scale zero to 3) exhibited a dose-related reduction. Significantly less beta 2-receptor agonist inhalations were used in the 450-mg group than in the placebo group. There was a statistically significant increase in headache and nausea with the doses 450 mg and 300 mg given twice daily during the first treatment week compared with 150 mg and placebo. Subsequent to the first week, there were no differences between the active treatments and placebo with respect to the incidence of these and other side effects. We conclude that oral enprofylline, in a dosage of 300 to 450 mg twice daily is an effective and well-tolerated drug that may be useful in the maintenance therapy of asthma.