<b><i>Introduction:</i></b> The predominant coagulation abnormalities in patients with coronavirus disease 2019 (COVID-19) suggest a hypercoagulable state and are consistent with uncontrolled clinical observations of an increased risk of venous thromboembolism. <b><i>Aim and Objectives:</i></b> To compare the effect of prophylactic versus therapeutic doses of enoxaparin in the treatment of severe cases of COVID-19 infection. <b><i>Materials and Methods:</i></b> This was a retrospective observational study conducted at Latifa hospital, Dubai. Fifty-nine patients enrolled from March to June 2020 and divided into 2 groups: patients who received the prophylactic dose of enoxaparin (group 1) and patients who received the therapeutic dose of enoxaparin (group 2). <b><i>Results:</i></b> The mean age of all cases was 47.2 ± 10.4 years, while the mean weight was 76.4 ± 13.4 kg. Males represented 79.7% of cases. Blood group “O” was the most frequent blood group (40.9%). None of the cases were smokers or using alcohol. Bronchial asthma, lung diseases, diabetes mellitus, hypertension, CKD, cardiac disease, thyroid disease, and immunodeficiency were present in 1.7, 1.7, 39, 27.1, 5.1, 1.7, 5.1, and 1.7% respectively. There was no significant difference between both study groups regarding personal and medical characteristics, except for hypertension where 35.9% of group 2 (therapeutic) cases were hypertensive compared to 10% of group 1 cases (prophylactic). There was a significant difference between both study groups regarding inflammatory markers improvement duration, duration of MV and O₂ support duration, with longer duration among (therapeutic) group 2 cases compared to group 1 cases (prophylactic). There was a highly significant difference between both study groups regarding ICU admission, as 64% of group 1 cases were admitted compared to 25% of group 1 cases. Similarly, 38.5% of group 2 cases needed MV compared to only 10% of group 1 cases, which was statistically significant. There was no significant difference between both groups regarding bleeding tendency and mortality (<i>p</i> value 0.54). <b><i>Conclusion:</i></b> Our results showed that use of prophylactic dose of enoxaparin might have some benefits compared to the therapeutic dose in terms of less duration of ICU and hospital stay, duration of oxygen support, need and duration of MV, and normalization of inflammatory markers. However, there was no significant difference between the 2 regimens regarding the mortality.