BACKGROUND Drug overdose is a public health crisis in the United States, due in part to the unintended consequences of increases in prescribing of opioid analgesics. Many clinicians evaluate risk markers for opioid-related harms when prescribing opioids for chronic pain; however, more data on predictive risk markers are needed. Risk markers are attributes (modifiable and non-modifiable) that are associated with increased probability of an outcome. This review aims to identify risk markers associated with fatal and non-fatal prescription drug overdose by synthesizing findings in the existing peer-reviewed and grey literature. Eligible cohort, case-control, cross-sectional, and case-cohort studies were reviewed and data were extracted for qualitative and quantitative synthesis. RESULTS Summary odds ratios (SOR) were estimated from 29 studies for six risk markers: sex, age, race, psychiatric disorders, substance use disorder (SUD), and urban/rural residence. Heterogeneity was assessed and effect estimates were stratified by study characteristics. Of the six risk markers identified, SUD had the strongest association with drug overdose death (SOR = 5.24, 95% confidence interval (CI) = 3.53 - 7.76), followed by psychiatric disorders (SOR = 3.94, 95% CI = 3.09 - 5.01), white race (SOR = 2.28, 95% CI = 1.93 - 2.70), the 35-44 year age group relative to the 25-34 year reference group (SOR = 1.52, 95% CI = 1.31 - 1.76), and male sex (SOR = 1.33, 95% CI = 1.17 - 1.51). CONCLUSIONS This review highlights fatal and non-fatal prescription drug risk markers most frequently assessed in peer-reviewed and grey literature. There is a need to better understand modifiable risk markers and underlying reasons for drug misuse in order to inform interventions that may prevent future drug overdoses.