Patients with moderate to advanced Parkinson's disease may have prominent levodopa-related motor fluctuations. In a double-blind crossover study, we compared the anti-Parkinson effects of standard Sinemet with a controlled-release formulation (Sinemet CR-4) in 23 patients with short-duration responses to standard Sinemet. With Sinemet CR-4, approximately half the patients who completed the study displayed a prolongation of their "on" response (optimal response to treatment), as assessed by monitoring individual drug-response cycles. A few patients experienced prolonged delays before the peak anti-Parkinson response developed to Sinemet CR-4. End-of-dose "wearing off" was favorably affected by Sinemet CR-4, but patients still had unpredictable "off" (parkinsonian) periods. Subjective ratings of Sinemet CR-4 varied, and 39% of patients who completed the study actually preferred standard Sinemet to the new formulation. We conclude that Sinemet CR-4 may benefit some patients with Parkinson's disease with a short-duration response to standard Sinemet; however, not all patients found it preferable to the standard formulation.