OBJECTIVES: To ascertain changes in Health related Quality of Life (HRQL) among young heroin users after one year follow-up. METHODS: Heroin users (18-30y) were recruited in outdoor settings in three Spanish cities (Barcelona, Madrid, Seville) from 2001 to 2003 and followed up, on average, 1.4(SD:0.6) years later. Standardised laptop interviews included socio-demographic data, drug use patterns, health related issues, the Severity of Dependence Scale (SDS) and the Nottingham Health Profile (NHP). For bivariate analyses, non parametric Mann-Whitney U and Kruskal-Wallis tests were used. Factors associated to NHP score changes over time were analysed through a multiple linear regression taking into account socio-demographic factors, consumption patterns and health related variables. RESULTS: A total of 628 subjects (72.5% males), mean age 27.9 (SD:3.4) years were followed (63.4%). Mean total NHP score improved, from 36.4 (SD:24.2) at baseline to 27.0 (SD:22.4) at follow-up. Variables associated with total NHP score worsening were HIV infection during follow-up, having experienced an overdose during the last 12 months and psychiatric treatment ever; conversely, total NHP score improved among those who got a job by the end of the study. Each additional substance with a weekly regular use and higher SDS scores for both cocaine and heroin, measured as a difference from baseline values, were also related to worsening total NHP score. We observed an interaction between severity of heroin dependence (as measured with SDS) and methadone maintenance treatment. The NHP total score only improved, with decreasing heroin SDS, among drug users in methadone maintenance treatment. CONCLUSIONS: HRQL improved over 12 months for young heroin users. The main variables independently related with HRQL were changes in heroin and cocaine SDS. Further holistic models taking into account social variables are needed.