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Background: During the ongoing opioid epidemic, Cuyahoga County (second largest in Ohio) reported overdose mortality rates (54/per 100,000) higher than the national average. Prior research demonstrates that people who use drugs often use alone but there is minimal research on people who died of overdose while using alone. The objective of this study is to examine sociodemographic, toxicologic, and injury characteristics, and emergency medical response to overdose decedents who died using drugs alone. Method: Data from the Cuyahoga County Medical Examiner's Office (2016–2020, N = 2944) on unintentional overdose deaths in adults was tabulated including socio-demographic, toxicologic, and injury-related information. Decedents using drugs alone were identified and compared to those not using alone via Chi-square and Fisher's exact tests. We further fit a multivariate logistic regression model to evaluate socio-demographic, toxicologic, and injury-related factors associated with increased odds of using alone. All results are reported with 95% confidence intervals. Result: Among decedents, 75% (n = 2205) were using drugs alone. Decedents using alone were more likely to be using drugs at home (p = 0.001) or be found dead at the scene (p < 0.001) and less likely to receive naloxone (p < 0.001) have other person/bystander, not using, present (p = 0.002). Using drugs at home (aOR = 1.61[1.19–2.20]) was associated with higher odds of using alone; and being married (aOR = 0.57[0.38–0.86]), having history of illicit drug use (aOR = 0.25[0.08–0.81]) and other person present, who was not using (aOR = 0.58[0.42–0.79]) were associated with lower odds of using alone. Conclusion: New harm reduction approaches targeting people using drugs alone are needed to reduce overdose deaths. [ABSTRACT FROM AUTHOR]