Background After surgical procedures, patients are at high risk of developing venous thromboembolism, clinically manifested as deep vein thrombosis (DVT) or pulmonary embolism (PE). Objective To evaluate the influence of polypharmacotherapy, comorbidity, drug treatments, packed red blood cells application, adequacy of thromboprophylaxis, and patient characteristics on the occurrence of DVT or PE in postsurgical patients. Setting The surgical department at Murska Sobota General Hospital, Slovenia. Methods In this retrospective case control study, the records of 286 surgical patients were analysed: DVT or PE group (n = 144) and control group (n = 142). The number of prescribed drugs and drug-drug interactions were reviewed, together with prescription of low-molecular-weight heparins. The odds ratios (OR) of risk factors for DVT or PE were calculated using a multivariable logistic regression model. Main outcome measure Risk factors assessment for the occurrence of DVT or PE in surgical patients. Results Polypharmacotherapy (OR 2.02, 95% CI 1.03-3.96, p = 0.040) and packed red blood cells application (OR 3.44, 95% CI 1.46-8.10, p = 0.005) were associated with an increased risk of PE or DVT after surgery. Inadequate thromboprophylaxis with low-molecular-weight heparins significantly increased the likelihood of DVT or PE (OR 2.50, 95% CI 1.41-4.43, p = 0.002). There were no differences between the groups concerning the treatment with nonsteroidal anti-inflammatory drugs, benzodiazepines or antipsychotics. Conclusions Patients with polypharmacotherapy and patients receiving red blood cells should be monitored more closely after surgery as they are more likely to develop DVT or PE.