We aimed to assess the effect of ageing and time since first heroin/cocaine use on cause-specific mortality risk and age disparities in excess mortality among heroin (HUs) and cocaine users (CUs) in Spain.

A cohort of 15,305 HUs and 11,905 CUs aged 15–49 starting drug treatment during 1997–2007 in Madrid and Barcelona was followed until December 2008. Effects of ageing and time since first heroin/cocaine use were estimated using a competing risk Cox model and the relative and absolute excess mortality compared to the general population through directly age-sex standardized rate ratios (SRRs) and differences (SRDs), respectively.

Mortality risk from natural causes increased with time since first heroin use, whereas that from overdose declined after having peaked in the first quinquennium. Significant effects of time since first cocaine use were not identified, although fatal overdose risk seemed higher in CUs after five years. Mortality risk from natural causes (HUs and CUs), injuries (HUs), and overdoses (CUs) increased with age, the latter without reaching statistical significance. Crude mortality rates from overdoses and injuries remained very high at age 40–59 among both HUs (595 and 217 deaths/100,000 person-years, respectively) and CUs (191 and 88 deaths/100,000 person-years). SRDs from all and natural causes were much higher at age 40–59 than 15–29 in both HUs (2134 vs. 834 deaths/100,000 person-years) and CUs (927 vs. 221 deaths/100,000 person-years), while the opposite occurred with SRRs.

The high mortality risk among HUs and CUs at all ages from both external and natural causes, and increased SRDs with ageing, suggest that high-level healthcare and harm reduction services should be established early and maintained throughout the lifetime of these populations.