A double-blind, randomized study compared the efficacy and safety of a controlled-release naproxen sodium formulation (Naprelan, Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania) 1,000 mg once daily; a conventional naproxen formulation (Naprosyn, Syntex Laboratories, Inc., Palo Alto, California) 500 mg BID; and placebo given for 12 weeks to 348 patients with rheumatoid arthritis (RA). This was followed by an open-label study to evaluate the safety of naprelan 1,000 mg once daily for an additional 9 months. In the double-blind phase of this study, the safety and efficacy of Naprelan 1,000 mg once daily were compared with those of Naprosyn 500 mg twice daily and placebo in 348 patients with RA. At the end of 12 weeks of treatment, Naprelan and Naprosyn were numerically superior to placebo in 3 of the 4 primary efficacy variables--physician's global assessment, patient's global assessment, and number of painful joints. Differences between Naprelan and placebo reached statistical significance for the patient's global assessment at Week 12 (Visit 7). Significantly more Naprosyn- than placebo-treated patients had at least 1 severe digestive system adverse event (AE); 1 drug-related AE; or 1 drug-related, digestive-system AE. There was no statistically significant difference in the number of AEs experienced by Naprelan-treated patients compared with those who received placebo. A total of 240 patients enrolled in the Naprelan open-label phase. As would be expected, patients initially treated with placebo showed significant improvement after starting Naprelan. Those initially receiving Naprelan or Naprosyn also maintained their improvement. The AE profile with Naprelan was similar to that reported in the double-blind phase. It was concluded that Naprelan 1,000 mg once daily was as effective as Naprosyn 500 mg BID in the treatment of RA and was particularly effective in relieving pain later in the day. The controlled-release formulation may also offer safety benefits.