Summary: After overnight drug withdrawal and in the fasting state, 11 patients with Parkinson's disease (PD) and a fluctuating response to chronic levodopa treatment were given, in random sequence on consecutive days, equivalent levodopa doses (with peripheral decarboxylase inhibitor) (a) as levodopa methyl ester (ME), (b) as Sinemet CR, or (c) as half the dose of ME together with a halved tablet of Sinemet CR. All patients turned ON rapidly after treatments a and c, but only half did so after treatment b. On period duration was longest after treatment c, intermediate after treatment a, and shortest after treatment b. Pharmacokinetic analysis in a subset of 6 patients revealed no significant difference between treatments a and c, although there was a trend for t1/2 to be longer after treatment c. We conclude that giving ME with a halved tablet of Sinemet CR provided a useful clinical balance between rapid onset and extended duration of action of at least the first levodopa intake of the day. In view of differing release profiles between whole and halved tablets of Sinemet CR, similar single-dose pharmacokinetic studies, followed by sequential-dose clinical studies, are indicated when Sinemet CR 125 tablets soon become available.