The multiple-dose (200 mg levodopa t.i.d.) pharmacokinetic profile of two controlled-release products of levodopa (Madopar HBS and Sinemet CR) was compared to conventional Madopar capsules in 18 healthy volunteers in a cross-over, randomized design. A pronounced controlled-release profile of the Madopar HBS and Sinemet CR product was demonstrated compared to conventional Madopar capsules with a significant (p < 0.001) decrease (-40 and -55%) in Cmax and a significant (p < 0.001) increase (+237 and +256%) in morning Cmin for the 200 mg t.i.d. dosage schedule. Almost equivalent bioavailability (85-90%) of levodopa was demonstrated for the controlled-release formulations relative to that of conventional Madopar capsules. The Madopar HBS formulation was bioequivalent with Sinemet CR with respect to levodopa, but it exhibited a moderately higher fluctuation index compared to Sinemet CR as a result of somewhat higher Cmax and lower Cmin values for the Madopar HBS formulation. 3-OMD (a metabolite of levodopa) levels were significantly (p < 0.05) higher for Madopar HBS and Madopar compared to Sinemet CR. The higher 3-OMD levels for the levodopa/benserazide combinations are consistent with a more potent decarboxylase inhibitory activity of benserazide as compared to carbidopa. The number of adverse events was highest for conventional Madopar (n = 18) compared to the controlled-release formulations (n = 12 for Sinemet CR and only 2 for Madopar HBS). A more efficient inhibition of dopamine formation from levodopa (resulting in higher 3-OMD levels) by Madopar HBS was consistent with the superior tolerability (especially for initial nausea) observed for the Madopar HBS formulation as compared to Sinemet CR.