Background/Objectives: Acutely ill patients in hospital are at high risk for thrombosis, even post-discharge. However, the safest and most effective strategy for thromboprophylaxis in such patients is still under debate. Our aim was to compare the subcutaneous use of low-dose prophylactic enoxaparin versus intermediate-dose tinzaparin. Methods: Patients in an internal medicine clinic of a tertiary hospital in Athens, Greece, with increased risk for thrombosis (PADUA score ≥ 4) received either intermediate-dose tinzaparin (8000 anti-Xa units) or 40 mg enoxaparin as thromboprophylaxis. Efficacy and adverse effects were evaluated and compared up to 14 days post-discharge. Results: A total of 251 patients who received tinzaparin were compared with 95 patients under enoxaparin thromboprophylaxis. No statistically significant difference was found in the number of bleeding and/or clinically evident thrombotic events between the two groups [6 versus 14 bleeding (p = 0.2603) events and 0 versus 1 venous thrombotic event (p = 0.999) in the enoxaparin and tinzaparin groups, respectively]. Moreover, no difference was found in length of stay [enoxaparin: 10 days (95%CI: 9–12 days); tinzaparin: 8 days (95%CI: 8–10 days, HR = 1.18, 95%CI: 0.91–1.54, p = 0.2] or mortality [11 deaths with enoxaparin (11.58%, 95%CI: 6.59–19.55%) and 50 deaths with tinzaparin (19.92%, 95%CI: 15.45–25.30%, OR: 1.9, 95%CI: 0.94–3.83, p = 0.069)]. The use of thromboprophylaxis for two weeks post-discharge did not result in any bleeding or clinically evident thrombotic events in either group. Conclusions: In our cohort, the use of intermediate-dose tinzaparin was similar to the use of low-dose enoxaparin for patients with a high PADUA score in terms of thrombotic and/or bleeding events.