ObjectiveTo examine sex differences in age-standardised rates (ASR) of overall and drug-specific drug poisoning deaths in Ireland between 2004 and 2017.DesignRepeated cross-sectional study.SettingDrug poisoning deaths in Ireland.ParticipantsNational Drug-Related Deaths Index and pharmacy claims database (Primary Care Reimbursement Service-General Medical Services) data from 2004 to 2017.Outcome measuresThe primary outcome was trends in drug poisoning death rates by sex. The secondary outcomes were trends in drug poisoning death rates involving (1) any CNS (Central Nervous System) depressants, (2) ≥2 CNS depressants and (3) specific drugs/drug classes (eg, prescription opioids, benzodiazepines, antidepressants, alcohol, cocaine and heroin) by sex. Joinpoint regression was used to examine trends, stratified by sex, in the ASR of drug poisoning deaths (2004–2017), change points over time and average annual percentage changes (AAPCs) with 95% CI.ResultsIncreased ASR for all drug poisoning deaths from 6.86 (95% CI 6.01 to 7.72) per 100 000 in 2004 to 8.08 (95% CI 7.25 to 8.91) per 100 000 in 2017 was mainly driven by increasing deaths among men (AAPC 2.6%, 95% CI 0.2 to 5.1), with no significant change observed among women. Deaths involving ≥2 CNS depressants increased for both men (AAPC 5.6%, 95% CI 2.4 to 8.8) and women (AAPC 4.0%, 95% CI 1.1 to 6.9). Drugs with the highest significant AAPC increases for men were cocaine (7.7%, 95% CI 2.2 to 13.6), benzodiazepines (7.2%, 95% CI 2.9 to 11.6), antidepressants (6.1%, 95% CI 2.4 to 10.0) and prescription opioids (3.5%, 95% CI 1.6 to 5.5). For women, the highest AAPC was for antidepressants (4.2%, 95% CI 0.2 to 8.3), benzodiazepines (3.3%, 95% CI 0.1 to 6.5) and prescription opioids (3.0%, 95% CI 0.7 to 5.3).ConclusionDrugs implicated in drug poisoning deaths vary by sex. Policy response should include prescription monitoring programmes and practical harm reduction information on polydrug use, especially CNS depressant drugs.