The relationships between magnitude of response to orally administered carbidopa/levodopa (CD/LD) and serum/cerebrospinal fluid (CSF) concentrations of levodopa (LD), 3-O-methyldopa (3-O-MD), and homovanillic acid (HVA) were studied in 15 patients with chronic LD-treated Parkinson disease. The degree of clinical benefit derived from a 25/250 tablet of CD/LD could not be correlated with absolute serum levels of LD, 3-O-MD or LD/3-O-MD ratios. CSF levels of LD and 3-O-MD were also not associated with improvement. CSF levels of HVA, however, did significantly correlate with magnitude of response to LD. Furthermore, CSF HVA levels were not dependent on previous LD dosage. Our data suggest that in chronic LD-treated patients, central factors related to the integrity of the nigrostriatal tract may be a more important determinant of magnitude of response to LD than peripheral elements affecting the amount of LD entering the central nervous system.