We tested acceptability and tolerability of long-acting injectable risperidone for methamphetamine (MA) dependence in an open trial with the hypothesis that participants would reduce MA use. Participants were also evaluated for changes in neurocognitive function and psychiatric symptomology. Participants with MA dependence (n = 34) entered a 7-day open-label run-in with oral risperidone. Participants who tolerated oral risperidone (n = 22) were begun on long-acting injectable risperidone 25 mg intramuscular medication with subsequent injections q 2 weeks to a total of 4 injections. Participants remained on oral risperidone during the first 3 weeks after initial injection. Participants were offered 8 weekly individual sessions of relapse prevention counseling. At baseline, participants reported using MA an average of 4.1 days per week (SD = 1.9). Estimated mean days of MA use per week while on injections was 1.0 (95% confidence interval = 0.6–1.4), with days of use decreasing significantly from baseline through week 8 (β = −0.27; 95% confidence interval: − 0.38–−0.16; P < 0.001). Mean week 6 risperidone + 9-OH risperidone plasma levels for participants abstinent from MA from weeks 5 to 8 (n = 7, 63.6%) were 18.8 ng/mL (SD = 6.6) compared with 12.3 (SD = 4.0) for those not abstinent (n = 4; P = 0.075). No serious adverse events occurred. Verbal memory improved at week 4 compared with baseline (P < 0.05). Participation in this trial of injectable risperidone was associated with reductions in MA use as well as some positive benefits on verbal memory. However, these results are limited by the use of an open trial design with a high dropout rate. Risperidone deserves further study in controlled trials as a pharmacotherapy for MA dependence.