The efficacy of 50 and 75 mg S(+)-ketamine administered daily by an iontophoresis-assisted transdermal drug delivery system was tested against placebo in a randomized, double-blind design in 33 patients with central neuropathic pain. At baseline and 1 week after the start of treatment subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analog scale (VAS), health status (Pain Disability Index and EQ-5D) and quality of life (SF-36). Safety assessment included incidence and intensity of adverse events. No significant differences in pain scores (VAS) were observed between the ketamine groups and placebo during the course of the trial. Corrected for baseline levels, daily 50 mg S(+)-ketamine did not improve patient's health status or quality of life compared with placebo treatment. However, daily 75 mg S(+)-ketamine showed significant improvements on the Pain Disability Index, on the EQ-5D, and on the SF-36 except for the role-physical functioning and general health perception. Iontophoretic administration of S(+)-ketamine was well tolerated with a low incidence of adverse events (mild and transient in nature, resolving spontaneously). Iontophoretic administration of S(+)-ketamine was not more effective than placebo treatment in reducing pain scores in patients with severe central neuropathic pain. However, iontophoretic administration of 75 mg S(+)-ketamine improved the health status and the quality of life in these patients.