Five parkinsonian patients with severe “on-off” effects from levodopa therapy also were given combination carbidopa/levodopa. Serial half-hourly measurements of plasma levels of dopa, 3-O-methyldopa, and homovanillic acid showed partial concordance between clinical fluctuation and plasma dopa levels in patients receiving levodopa alone or in combination with carbidopa. The combination therapy does not lessen “on-off” effects except when administered in greater and more-frequent doses, which are permitted by the improved gastrointestinal tolerance with carbidopa/levodopa. A single intramuscular injection of pyridoxine has no clinical effect and slightly lowers subsequent plasma dopa only in the absence of carbidopa. Possible biochemical mechanisms are discussed.