Background Patients with active cancer have a 4–sevenfold increased risk for venous thromboembolism (VTE) especially during systematic anticancer treatment. Simultaneously, surgery is an additional risk factor. Methods The Metaxas’s Hospital THromboprophylaxis program in Oncological & Surgical Patients (MeTHOS) is a prospective, phase IV, observational, non-interventional cohort study, aiming to record the thromboprophylaxis practice patterns in high-risk active cancer patients undergoing surgical and/or chemotherapy treatment. Results We are reporting results from 291 ambulatory patients (median age: 67 years, Q1–Q3: 59–73 years, 54.6% males) who received anti-neoplastic treatment and administered thromboprophylaxis. 59.8% had cardiovascular disease (mostly hypertension), 76.6% were reported as having at least one comorbidity, while 27.5% and 15.8% accumulated two and three comorbidities, respectively. 94.9% of the patients were receiving highly thrombogenic agents such as platinum-based agents, 5-FU, immunotherapy, antiangiogenics/anti-VEGF, or erythropoietin. 26.5% of the patients were initially surgically treated. In terms of anticoagulation, all patients were treated with tinzaparin (fixed dose, 10,000 Anti-Xa IU, OD). The median anticoagulation duration was 6.2 months. Six thrombotic events were observed (2.06%, 95% CI: 0.76–4.43%): 5 were DVT, and one PE. With respect to safety, 7 bleeding events occurred (2.6%, 95% CI: 1.0–5.3%); 6 of them were minor. Conclusions Thromboprophylaxis with LMWH in patients with active cancer and high thrombotic burden was safe and effective. Intermediate dose of tinzaparin seems to be an appropriate agent for cancer-associated thromboprophylaxis management. Clinical trial registration ClinicalTrials.gov: NCT04248348.