Background There is increasing public health concern regarding the addiction and dependence potential of tramadol. Objective This study sought to determine factors associated with tramadol abuse among commercial drivers and assistants in the Accra Metropolitan Area of Ghana. Patients and MethodsThe study employed a mixed-method quantitative and qualitative approach. It involved a crosssectional survey and focus group discussions with commercial drivers and assistants at selected transport terminals in Accra. Data on abuse, reasons for abuse, sources of supply, and factors associated with abuse were collected from the respondents and analyzed using STATA and Nvivo, as appropriate. Results Of the 458 study participants, 114 (24.9%) indicated that they abused tramadol. The mean (± standard deviation) age of those who abused tramadol (25.14 ± 5.87 years) was significantly lower than that of nonabusers (28.23 ± 9.6 years), t(456) = -3.60; p = 0.001. The level of risk of dependence on tramadol among the abusers was high, as 49.1% (56/114) of abusers were estimated to have a composite risk score of ≥ 27. Various socioenvironmental factors, including tension or fighting among family members (adjusted odds ratio [AOR] 7.73; 95% confidence interval [CI] 3.33-17.98; p < 0.001), abuse of drugs by a family member (AOR 2.27;; p = 0.007), and having a friend who abused drugs (AOR 2.17; 95% CI 1.22-3.89; p = 0.009) were associated with tramadol abuse. Reasons given for using tramadol included pain relief and sexual enhancement. ConclusionThe level of tramadol abuse and dependence was high. This calls for interventional programs, including health education, as dependency on tramadol has dire consequences on productivity.