OBJECTIVES: Opioid dependence not only impacts health outcomes and healthcare costs in the US, but also imposes a large economic burden on the workplace. Estimated lost workplace productivity accounts for the largest share (~$25.6 billion or 45.6%) of total societal costs.This study evaluated the impact of extended-release naltrexone (XR-NTX), available as a once-monthly injectable treatment option for preventing relapse to opioid dependence, on self-reported substance use and employment status, in patients treated in a real-world, naturalistic study. METHODS: Analysis of an open-label, single-arm, US multicenter registry of adult, opioid dependent outpatients initiating XR-NTX treatment following detoxification. Substance use and employment status in the previous 28 days were collected via the National Treatment Agency Treatment Outcomes Profile (TOP). Analyses were conducted in patients with data available from baseline until at least 6 months of XR-NTX treatment. Intra-subject paired hypothesis tests were conducted. RESULTS: A total of 112 (26.6%) of 403 enrolled registry patients had over 6 months of on-treatment follow-up, with 99 (24.6%) completing Month 6 assessments. Abstinence rates for opioids (45.5% to 95.0%; p=0.001), alcohol (64.7% to 78.8%; p=0.006), and stimulants (crack, cocaine and amphetamine) (82.8% to 96.0%; p=0.002) significantly increased from baseline to Month 6. Baseline to Month 6 unemployment rates significantly decreased from 53.5% to 37.4% (p=0.005). Among 53 patients unemployed at baseline, the majority (55.3%) reported employment at Month 6, with 17.0% indicating working 1-16 days and 28.3% working >16 days in the prior 28 days. CONCLUSIONS: In this real-world registry, XR-NTX was associated with increased rates of opioid abstinence, as demonstrated in previous controlled studies. While limitations include the uncontrolled design and the sample subset with 6 months of data, this is the first study to find that patients in XR-NTX treatment showed reductions in overall drug use, with concurrent increased employment.