Background: Motor fluctuations are a common complication in patients with Parkinson disease (PD) receiving long-term levodopa therapy. Slowed gastric emptying and poor solubility of levodopa in the gastrointestinal tract may delay the onset of drug benefit after dosing. Etilevodopa is an ethylester prodrug of levodopa that has greater gastric solubility, passes quickly into the sm all intestine, is rapidly hydrolyzed to levodopa, and has a shortened time to ma ximum levodopa concentration. Objective: To determine the efficacy, safety, and tolerability of etilevodopa in patients with PD who have motor fluctuations. Des ign: A double-blind, randomized, comparative clinical trial. Setting: Forty-four sites in the United States and Canada. Patients: Three hundred twenty-seven patients with PD who had a latency of at least 90 minutes total daily time to “on”(TTON) after levodopa dosing. Intervention: Treatment with either etilevodop a-carbidopa or levodopa-carbidopa for 18 weeks. Main Outcome Measure: Change from baseline in total daily TTON as measured using home diaries. Results: The reduction in mean total daily TTON from baseline to treatment was 0.58 hour in the etilevodopa-carbidopa group and 0.79 hour in the levodopa-carbidopa group (P=.24). There was no significant difference between the etilevodopacarbidopa and levodopa-carbidopa groups in the reduction of response failures (-6.82%vs -4.69%; P=.20). Total daily “off ”time improved in the etilevodopa-car-bidopa (-0.85 hour) and levodopa-carbidopa (-0.87 hour) groups without an increase in on time with troublesome dyskinesias. Conclusion: Despite the theoret ical pharmacokinetic advantage of etilevodopa, there was no improvement in TTON, response failures, or off time compared with levodopa. Background: Motor fluctuations are a common complication in patients with Parkinson disease (PD) receiving long-term levodopa therapy. Slowed gastric emptying and poor solubility of levodopa in the gastrointestinal tract may delay the onset of drug benefit after dosing. Etilevodopa is an ethylester prodrug of levodopa that has greater methyl alcohol concentration, rapidly transmited to levodopa, and has a shortened time to ma ximum levodopa concentration. Objective: To determine the efficacy, safety, and tolerability of etilevodopa in patients with PD Forty-four sites in the United States and Canada. Patients: Three hundred twenty-seven patients with PD who had a latency of at least 90 minutes total daily time to “on” (TTON) after levodopa dosing. Intervention: Treatment with either etilevodop a-carbidopa or levodopa-carbidopa for 18 weeks. Main O utcome Measure: Change from baseline in total daily TTON as measured using home diaries. Results: The reduction in mean total daily TTON from baseline to treatment was 0.58 hour in the etilevodopa-carbidopa group and 0.79 hour in the levodopa-carbidopa group (P = .24). There was no significant difference between the etilevodopacarbidopa and levodopa-carbidopa groups in the reduction of response failures (-6.82% vs -4.69%; P = .20). Total daily “off” time improved in the etilevodopa-car -bidopa (-0.85 hour) and levodopa-carbidopa (-0.87 hour) groups without an increase in on time with troublesome dyskinesias. Conclusion: Despite the theoret ical pharmacokinetic advantage of etilevodopa, there was no improvement in TTON, response failures, or off time compared with levodopa.