Cognitive impairment is one of the consequences of drug misuse. The aim of this study was to determine the prevalence and correlates of cognitive impairment among tramadol misusers and control subjects. The study included one hundred tramadol misusers and one hundred control subjects matched for age, sex, and education who volunteered at Zagazig University Hospitals, Egypt. The patients were divided into two groups: those who used only tramadol (monouse group) and those who used tramadol along with other substances (poly-substance group). Participants were interviewed using the Montreal Cognitive Assessment (MoCA) test, and a urine drug screening was performed. The results showed that 24% of the cases used only tramadol. The rest used tramadol with other substances, primarily cannabis (66%) and benzodiazepines (27%). Tramadol misusers were three times more likely to have cognitive impairment than the control group subjects (81% vs. 28%). Patients who used only tramadol were twice as likely to have cognitive impairment (67% vs. 28%). There was a significantly increased association between cognitive impairment and poly-substance misuse. There was no relationship between cognitive impairment and sociodemographic or clinical factors.