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Background: Although preclinical models reveal the neurobiological pathways altered through opioid abuse, comprehensive assessments of gene expression in human brain samples are needed. Moreover, less is known about gene expression in response to fatal overdose. The primary goal of the present study was to compare gene expression in the dorsolateral prefrontal cortex (DLPFC) between brain samples of individuals who died of acute opioid intoxication and group-matched controls., Methods: Postmortem tissue samples of the DLPFC from 153 deceased individuals ( M age  = 35.4; 62% male; 77% European ancestry). Study groups included 72 brain samples from individuals who died of acute opioid intoxication, 53 psychiatric controls, and 28 normal controls. Whole transcriptome RNA-sequencing was used to generate exon counts, and differential expression was tested using limma-voom . Analyses were adjusted for relevant sociodemographic characteristics, technical covariates, and cryptic relatedness using quality surrogate variables. Weighted correlation network analysis and gene set enrichment analyses also were conducted., Results: Two genes were differentially expressed in opioid samples compared to control samples. The top gene, NPAS4 , was downregulated in opioid samples (log 2 FC = -2.47, adj. p  = .049) and has been implicated in opioid, cocaine, and methamphetamine use. Weighted correlation network analysis revealed 15 gene modules associated with opioid overdose, though no intramodular hub genes were related to opioid overdose, nor were pathways related to opioid overdose enriched for differential expression., Conclusions: Results provide preliminary evidence that NPAS4 is implicated in opioid overdose, and more research is needed to understand its role in opioid abuse and associated outcomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s). Published by Elsevier B.V.)