To study the prevalence of perceived high stress among methadone maintenance treatment (MMT) patients, and whether stress can predict outcome, and whether stress may improve during treatment, we studied a sample of 107 MMT patients using Perceived Stress Scale (PSS) questionnaires. We studied if PSS scores on admission predict long-term retention, and we monitored stress indices (PSS, heart rate variability, saliva cortisol) on admission, 6 and 12 months later, to measure changes. Variables included demographic data, history of adverse events, and urine test. A sample of 79 (73.8%) males and 28 (26.2%) females whose age at opioid use onset was 22.1+/-7.2 years and age at study onset 50.5+/-10.8 years was studied for PSS. Both high and very-high PSS patients characterized (logistic regression) as abusing benzodiazepine, and with history of depressive symptoms. The very-high PSS group on admission (n=29) had shorter cumulative retention (1.8 years, 95%%CI 1.2-2.4) compared with 50 others (2.8 years, 95%%CI 2.3-3.3, p=0.03). Monitoring stress indices among 25 patients found that no-benzodiazepine and cocaine use on admission, opioid discontinuation after 6 months, and any substance discontinuation after a year were associated with stress reduction. Conclusion: stress level appears to normalize among MMT patients if no other substance is abused.