Background Mental disorder (MD) and problem, hazardous or harmful substance use (SUD) are associated with poorer than average health and greater mortality. We analysed routine data to estimate incidence of co-occurring (CC) MD and SUD, and to estimate all-cause mortality and survival with CC, a single MD or SUD diagnosis or neither condition (NC), in young people aged 11-25 in Wales, UK. Methods A retrospective population-based electronic cohort study using data from the Secure Anonymised Information Linkage (SAIL) Databank. Participants were 958,603 individuals aged 11-25 between 2008 and 2017, with a subset for mortality and survival analysis of 465,242 individuals born between 1983 and 1997 and present in the data on 1st January 2008. Incidence was defined as date of first recorded occurrence of a CC code. Incidence and observed unadjusted mortality were reported as rates per 1,000 person-years at risk (PYAR). We plotted Kaplan-Meier survival curves and carried out Cox regression to estimate hazard ratios for risk of death by condition group (CC; MD or SUD only; NC). Results CC incidence in primary care significantly decreased, from 2.5/1,000 PYAR (95% CI 2.3-2.6) in 2008 to 2.1/1,000 (95% CI 2.0-2.2) in 2017 (Incidence rate ratio (IRR) = 0.9, 95% CI 0.8-1.0, p=0.01), and in hospital admissions remained stable, from 2.3/1,000 (95% CI 2.1-2.4) in 2008 to 2.2/1,000 (95% CI 2.0-2.3) in 2017 (IRR = 1.0, 95% CI 0.9-1.1). Higher incidence was associated with male sex, older age and greater deprivation.Observed unadjusted mortality rates for CC (1.4/1,000 PYAR, 95% CI 1.2-1.5) and SUD only (1.1/1,000, 95% CI 0.9-1.4) were significantly higher than for MD only (0.4/1,000, 95% CI 0.3-0.4) and no condition (NC) (0.3/1,000, 95% CI 0.2-0.3). Risk of death was significantly higher for CC (HR = 8.7, 95% CI 7.5-10.0, p<0.001), SUD only (HR = 4.5, 95% CI 3.4-5.9, p<0.001) and MD only (HR = 2.7, 95% CI 2.4-3.1, p<0.001), compared with NC.Conclusions Male sex, older age and greater deprivation were associated with significantly higher CC incidence. CC, and also SUD or MD only, were associated with greater risk of death, compared with individuals with NC.