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<b><i>Background:</i></b> The aim of the study was to estimate the lethality of opioid overdose among young heroin users. <b><i>Methods:</i></b> A prospective community cohort study was conducted in Barcelona and Madrid, Spain. Participants included 791 heroin users aged 18-30 years who were followed up between 2001 and 2006. Fatal overdoses were identified by record linkage of the cohort with the general mortality register, while non-fatal overdoses were self-reported at baseline and follow-up interviews. The person-years (py) at risk were computed for each participant. Fatal and non-fatal overdose rates were estimated by city. Transition towards injection shortly before the overdose could not be measured. Overdose lethality (rate of fatal overdose in proportion to total overdose) and its 95% CI was estimated using Bayesian models. <b><i>Results:</i></b> The adjusted rates of fatal and non-fatal opioid overdose were 0.7/100 py (95% CI: 0.4-1.1) and 15.8/100 py (95% CI: 14.3-17.6), respectively. The adjusted lethality was 4.2% (95% CI: 2.5-6.5). <b><i>Conclusions: </i></b>Four out of 100 opioid overdoses are fatal. These are preventable deaths that could be avoided before or after the overdose takes place. Resources are urgently needed to prevent fatal opioid overdose.

<b><i>Background/Aims:</i></b> Non-fatal opioid overdose (NFOO) and major depression (MD) are highly prevalent in heroin users. Many risk factors are known for NFOO, but studies in non-clinical samples on its relationship with MD are lacking. We aimed to examine this relationship in a street-recruited sample, controlling for potential well-known confounders. <b><i>Methods:</i></b> A cross-sectional study in 452 heroin users street-recruited by chain referral methods in three Spanish cities. Eligibility criteria were: age ≤30 years, heroin use at least 12 days in the last year and at least once in the last 3 months. Depression was assessed using the Composite International Diagnostic Interview. A precise definition of NFOO was used. Adjusted odds ratios (AORs) for the NFOO predictors were obtained by logistic regression. <b><i>Results:</i></b> The prevalence of NFOO and MD in the last 12 months was 9.1 and 23.2%, respectively. After adjusting for potential confounders, NFOO and MD were significantly associated (AOR 2.2; 95% CI 1.01-4.74). Other associated factors were imprisonment (AOR 4.1; 95% CI 1.4-12.1), drug injection (AOR 6.7; 95% CI 2.4-18.4) and regular use of tranquillisers/sleeping pills (AOR 2.9; 95% CI 1.16-7). <b><i>Conclusions:</i></b> Drug and mental health treatment facilities should consider the relationship between MD and NFOO when contacting and treating heroin users. Imprisonment, drug injection and use of tranquillisers/sleeping pills are also risk factors for NFOO.