Mental health and substance misuse disorders are associated with unnatural deaths in prisoners. Deaths in Irish prisons between 2009 and 2014 were retrospectively analysed using coroner's findings, including post-mortem toxicology. There were 69 deaths in custody, 38 of which met inclusion criteria. All deaths by overdose (16) were positive for illicit drugs; 53% of deaths (8 of 15) due to hanging were also positive for illicit drugs, and 29% of deaths (2 of 7) from other causes were toxicology positive. In conclusion, 26 unnatural deaths (68%) were associated with use of illicit drugs, which are a major contributory factor to deaths of prisoners.