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To determine the contribution of heroin, prescription opioids, cocaine and alcohol/drug combinations to the total overdose death rate and identify changes in drug overdose patterns among New Mexico subpopulations.We analyzed medical examiner data for all unintentional drug overdose deaths in New Mexico during 1990–2005. Age-adjusted drug overdose death rates were calculated by sex and race/ethnicity; we modeled overall drug overdose death adjusting for age and region.The total unintentional drug overdose death rate in New Mexico increased from 5.6 per 100 000 in 1990 to 15.5 per 100 000 in 2005. Deaths caused by heroin, prescription opioids, cocaine and alcohol/drug combinations together ranged from 89% to 98% of the total. Heroin caused the most deaths during 1990–2005, with a notable rate increase in prescription opioid overdose death during 1998–2005 (58%). During 1990–2005, the 196% increase in single drug category overdose death was driven by prescription opioids alone and heroin alone; the 148% increase in multi-drug category overdose death was driven by heroin/alcohol and heroin/cocaine. Hispanic males had the highest overdose death rate, followed by white males, white females, Hispanic females and American Indians. The most common categories causing death were heroin alone and heroin/alcohol among Hispanic males, heroin/alcohol among American Indian males and prescription opioids alone among white males and all female subpopulations.Interventions to prevent drug overdose death should be targeted according to use patterns among at-risk subpopulations. A comprehensive approach addressing both illicit and prescription drug users, and people who use these drugs concurrently, is needed to reduce overdose death.