•89% of drug deaths were overdoses; 11% had injuries as immediate cause of death.•Prescription opioid involvement in deaths decreased by half in 2015–2017.•Fentanyl, heroin and cocaine now in top five drugs involved in 2015–2017 WV deaths.•Ten different fentanyl analogs identified (total 427 times) from 2015 to 2017.•Increasing recent involvement of methamphetamine in deaths is also of concern. To describe and analyze the involvement of fentanyl and fentanyl analogs (FAs) in drug-related deaths in West Virginia (WV), United States. Retrospective analyses of all WV drug-related deaths from 2005 to 2017 were performed, including comparisons of demographic and toxicological characteristics among total deaths, deaths in which fentanyl/FAs were present, deaths in which they were absent, heroin-related deaths, and prescription opioid-related deaths. Most of the 8813 drug-related deaths were overdoses, with about 11% resulting from transportation/other injuries in which drugs were contributors. Prescription opioid presence (without fentanyl) decreased by 75% from 2005–14 to 2015–17 (3545 deaths to 859 deaths, respectively), while fentanyl involvement in the deaths increased by 122% between these periods (487 to 1082 deaths). Ten FAs were identified (427 instances) after 2015. Alprazolam and ethanol were among the top five most frequently identified substances across years. Fentanyl, heroin and cocaine replaced oxycodone, diazepam and hydrocodone in the top five beginning in 2015. Few decedents had a prescription for fentanyl after 2015, with fewer prescriptions also present for other controlled substances identified. Fentanyl, rapidly emerging FAs, and other illicit drugs in recent years pose a serious health threat even though prescription opioid-related deaths decreased over the same time period.