The cause of motor fluctuations occurring during constant-rate levodopa infusions is unknown. We examined whether known pharmacokinetic factors could explain the fluctuations and looked for clues to pharmacodynamic causes. Eleven subjects with stage III-V Parkinson's disease (PD) and a fluctuating response to levodopa underwent constant-rate infusions for 36-110 h. Levodopa, 3-O-methyldopa (3-OMD), and plasma large neutral amino acids (LNAAs) were measured at 2- to 6-h intervals and PD was monitored hourly from 07:00 to 22:00 h with tapping speed. Ten subjects had motor fluctuations during the infusions. Zero to 68% of the variability of tapping speed could be explained by variation in plasma LNAA concentrations in individual subjects. Fluctuations occurred more commonly later in the day, which may be related to the tendency for LNAAs to increase during the day. Motor fluctuations were not associated with minor variations in levodopa or 3-OMD concentrations. Fluctuations during constant infusions were more marked in patients using larger daily doses of oral levodopa; severity of PD did not predict fluctuations during the infusions. There was no trend for fluctuations or dyskinesia to decrease or increase during several days of constant-rate levodopa infusion. A portion of motor fluctuations occurring during constant levodopa infusions can be explained by peripheral pharmacokinetic mechanisms. Fluctuations are more prominent in subjects who have taken larger daily doses of levodopa, implicating pharmacodynamic factors as well.