The optimal anticoagulant treatment regimen in hospitalized coronavirus disease 2019 (COVID-19) patients is uncertain. This study aimed to compare the rates of disease progression and mortality in patients treated with low-molecular-weight heparin (LMWH) according to baseline d-dimer levels and in those who received a fixed-dose regimen irrespective of the d-dimer level. This was a retrospective analysis of all patients admitted to a university hospital for COVID-19 pneumonia during a 1-year period. The protocol for d-dimer-driven therapy (on-protocol) was as follows: prophylactic dose when the baseline level is <1000 ng/mL, intermediate dose when the level is between 1000 and 3000 ng/mL, and therapeutic dose when the level is >3000 ng/mL. We compared the progression and mortality rates between the on-protocol and off-protocol treatment groups. The offprotocol group consisted of patients that received a fixed-dose LMWH regimen, which was not in accordance with the defined protocol. Of 384 patients (mean age 61.5 ± 15.9 years, 216 male), 294 patients with complete data composed the study group, and 174 patients were treated on-protocol and 120 patients were treated off-protocol. The on-protocol group had lower C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH), and d-dimer levels and higher SpO2/FiO2 levels at admission. Disease progression developed in 45/174 on-protocol patients (25.9%) vs. 53/120 off-protocol patients (44.2%) during the follow-up (P = .001), and mortality was 29 (16.7%) vs. 32 (26.7%), respectively (P = .041). Logistic regression analysis was performed and included age, presence of comorbidities, LMWH regimen, baseline SpO2/FiO2, CRP, and LDH levels as independent variables. The presence of cardiac comorbidity, age, CRP, and LDH levels, but not the LMWH treatment regimen, were associated with both disease progression and mortality. A d-dimer-driven LMWH treatment protocol is not associated with better clinical outcomes in hospitalized COVID-19 patients.