Methamphetamine has become a major public health issue globally, particularly in the United States. Despite this, no effective pharmacotherapy for methamphetamine abuse has been developed to date. This 6-week, open-label pilot clinical trial examined the safety and tolerability of modafinil up to 400 mg/d in 8 methamphetamine-dependent individuals. Subjects were inducted onto modafinil at 400 mg/d for more than 3 days and remained on 400 mg/d for 4.5 weeks. Participants received weekly blister packs and underwent weekly individual cognitive behavioral therapy. Adjunctive contingency management procedures were used to enhance retention. Vital signs and supervised urine samples were obtained thrice weekly, and self-reported drug use and Hamilton anxiety and depression ratings were completed once weekly. Eight subjects (50% female, 100% white, aged 35-52 years) were enrolled. Four completed the 6-week study, 3 completed a portion, and 1 withdrew consent before completing intake. Results showed that systolic blood pressure (t = 1.09, P = 0.28), diastolic blood pressure, (t = 1.18, P = 0.24), and heart rate (t = 1.55, P = 0.13) did not change over time. Scores on the modafinil side effects checklist (t = −2.63, P = 0.01), Hamilton anxiety scale (t = −2.50, P = 0.018), and Hamilton depression scale (t = −3.25, P = 0.003) all decreased over time. The proportion of urine positive for amphetamines did not change over time (t = −0.52, P = 0.61), whereas self-reported methamphetamine use did (t = −2.86, P < 0.005). These results suggest that modafinil at 400 mg/d is safe and tolerable for methamphetamine-dependent individuals.