Understanding the mortality of drug users using multiple substances is helpful in preventing the harmful effects of polydrug use. We examined overall and cause-specific mortality and differences in mortality based on social background among people suspected of driving under the influence and testing positive for multiple substances (DUIMS) compared with the general Finnish population. Methods: Register data from 785 DUIMS during 2003–2006 were studied, with a reference population (n = 25,381) drawn from the general Finnish population. The effect of DUIMS on all-cause and cause-specific mortality was estimated using a Poisson regression model. Results: DUIMS had an increased risk of death compared with the general population (MRR 5.3, 95% CI 4.2–6.6). The most common causes of death in DUIMS were poisonings (37.9%) and suicides (13.6%), whereas in the reference population these were cardiovascular diseases (30.8%) and cancer (26.6%). The cause-specific risk of death among DUIMS was higher in all observed causes of death, except for cancer. The effect of DUIMS on mortality was modified by age, employment status and marital status; DUIMS was associated with an elevated risk of death especially in younger age groups and in singles.