Summary:Levodopa ethyl ester (LDEE), a highly soluble prodrug of levodopa, was synthesized and administered to mice and rats subcutaneously or intraperitoneally. Striatal levels of levodopa, dopamine, and the dopamine metabolite 3,4‐dihydroxyphenylacetic acid (DOPAC) were determined using high‐performance liquid chromatography with electrochemical detection and compared with those obtained after intraperitoneal injections of levodopa. LDEE injections produced significant and rapid elevations of striatal levodopa, dopamine, and DOPAC, which were similar to those achieved after levodopa administration, with similar dose‐response curves. The elevations achieved by LDEE given s.c. were higher than those achieved after i.p. administration and lasted for longer periods. In addition, intraperitoneal administration of levodopa or LDEE to rats with unilateral 6‐hydroxydopamine (6‐OHDA) nigral lesions produced similar contraversive circling responses. We suggest that LDEE may be a beneficial antiparkinsonian agent. It has potential pharmacokinetic advantages that are superior to those of levodopa itself, and its subcutaneous administration may become an effective rescue strategy to overcome “off” situations in patients with Parkinson's disease and response fluctuations.