OBJECTIVE: To determine if modafinil, a putative treatment for cocaine dependence, influences the pharmacokinetics of intravenous cocaine in otherwise healthy cocaine-dependent volunteers. METHODS: Cocaine 20 or 40 mg was administered intravenously on consecutive days over 1 minute at baseline and after modafinil administration at each of two dosages of 400 and 800 mg/day for 7 days. RESULTS: Twelve subjects completed the clinical protocol. Compared with baseline, the cocaine peak plasma concentration was decreased after both the 20 and 40 mg cocaine infusions, but the reduction was only statistically significant after the 40 mg cocaine infusion (p < 0.01 after modafinil 400 mg/day; p < 0.05 after modafinil 800 mg/day). The area under the cocaine plasma concentration-time curve from 0 to 180 minutes (AUC180) was significantly decreased by modafinil administration (p < 0.01 and p < 0.001 for modafinil 400 and 800 mg/day, respectively, for the cocaine 20mg dose; p < 0.001 for the cocaine 40 mg dose at both modafinil levels). There were no significant changes in total AUC, clearance or elimination half-life of cocaine. CONCLUSION: This study did not find evidence for a harmful pharmacokinetic interaction between modafinil and cocaine. In contrast, long-term administration of modafinil significantly decreased systemic exposure to cocaine during the first 180 minutes following intravenous cocaine administration.