Aims To examine mortality rates and causes of death among a cohort of substance-using mothers and to identify risk factors that predict mortality. Design, setting, participants This is a prospective study of a cohort of 4447 substanceusing mothers (pregnant or parenting) who were enrolled during 2000-02 in 40 drug abuse treatment programs across California. Methods All mothers were assessed at baseline using the Addiction Severity Index. Mortality data were obtained from the National Death Index and causes of death were coded using ICD-10. Standardized mortality ratios (SMR) were calculated relative to women in the general population adjusted for age. Proportional hazard (Cox) regression was used to identify risk factors predicting death. Results At the end of 2010, 194 deaths were confirmed, corresponding to a crude mortality rate of 4.47 per 1000 person-years and SMR of 8.4 (95% confidence interval: 7.2-9.6). Drug overdose (28.8%), cardiovascular disease (10%), and alcohol or drug disorders (8.9%) were the leading causes of death. Baseline factors associated with higher mortality included older age, being white (relative to African American or Hispanic), heroin, alcohol, cocaine or marijuana (relative to methamphetamine) as the primary drug problem, drug injection and greater severity of employment, medical/ health and psychiatric problems. Conclusions Substance-using mothers have 8.4 times the mortality than that observed among US women of similar age. Greater severity of employment, medical/ health and psychiatric problems contributed to the elevated mortality.