Eleven patients with solid tumors for whom effective therapy was not available entered a phase I study of mitonafide given as a short intravenous (i.v.) infusion daily for 3 consecutive days. The initial dose level was selected according to the experience from another phase I study using a 5-day administration schedule. Six patients entered the first dose level (180 mg/m2/day x 3 days) and 4 of them had grade 3-4 leukopenia. This level was considered to be the maximum tolerated dose (MTD) and no further dose escalations were attempted. The following 5 patients received a dose approximately 10% inferior to the previous one (160 mg/m2/day x 3 days). Three of them had grade 3-4 neutropenia. Three partial responses were observed in total. After inclusion of 11 patients, an unexpected toxicity, central nervous system (CNS) toxicity, consisting of severe loss of memory, temporospatial disorientation and high integrative function impairment was observed in 5 patients (46%). A median patients' follow-up of 3 months after treatment discontinuation showed that these alterations were progressive and not reversible. This disabling toxicity prompted us to an early study interruption. In conclusion, mitonafide, when administered as a short 3-day i.v. infusion, can induce severe and irreversible CNS toxicity. Nevertheless, since antitumor activity has been observed, further development of the drug is recommended with different schedules of administration that have shown not to produce neurotoxicity, i.e., 5-day continuous infusion.