Background <p>Coagulopathy is a significant complication in pediatric COVID-19, yet optimal anticoagulation dosing in children remains uncertain due to the lack of randomized controlled trials. This study aimed to compare the efficacy and safety of prophylactic versus therapeutic anticoagulation dosing in children hospitalized with SARS-CoV-2 pneumonia.</p> Methods <p>A retrospective observational study was conducted at Children’s Hospital 1 in Ho Chi Minh City, Vietnam, from July 2021 to May 2022. Pediatric patients with confirmed COVID-19 who received enoxaparin were included. Following the national paediatric protocol, patients were stratified by enoxaparin dose into a prophylactic-dose group (0.5&#xa0;mg/kg every 12&#xa0;h; total ≤ 1&#xa0;mg/kg/day) and a therapeutic-dose group (1&#xa0;mg/kg every 12&#xa0;h; total &gt; 1&#xa0;mg/kg/day). Because thrombotic events and deaths were rare, length of hospital stay and changes in inflammatory and coagulation biomarkers were examined as exploratory surrogate outcomes, while in-hospital mortality and bleeding events were reported descriptively. Multivariable regression and inverse probability of treatment weighting (IPTW) were used to reduce, but not eliminate, confounding by indication.</p> Results <p>Of 181 eligible patients, 140 were included (99 prophylactic-dose, 41 therapeutic-dose). The therapeutic-dose group had a higher proportion of severe/critical disease (82.9% vs. 55.6%, <i>p</i> = 0.003). After multivariable adjustment, therapeutic dosing was not associated with a significant difference in length of hospital stay (β = 0.041, 95% CI: −0.165 to 0.246, <i>p</i> = 0.698), changes in D-dimer (β = 0.195, <i>p</i> = 0.797), C-reactive protein (β = 0.122, <i>p</i> = 0.985), or ferritin levels (β = 191.6, <i>p</i> = 0.509). No thrombotic events occurred in either group. In-hospital mortality was low (5/140, 3.6%) and did not differ between the prophylactic- and therapeutic-dose groups (4.0% vs. 2.4%, <i>p</i> = 1.000). Major bleeding was confined to two patients (4.9%) in the therapeutic-dose group; with only two events, no reliable safety comparison between dosing strategies was possible. IPTW sensitivity analysis was consistent with these results.</p> Conclusions <p>After adjusting for disease severity and other confounders, we did not detect a statistically significant difference in efficacy outcomes between prophylactic- and therapeutic-dose anticoagulation. Because of the retrospective design, small sample, strong confounding by indication, and the absence of thrombotic events, these findings are exploratory and hypothesis-generating; the lack of a statistically significant difference should not be interpreted as evidence of equivalence between the two strategies. Prospective, adequately powered studies are needed before any dosing strategy can be recommended for children with SARS-CoV-2 pneumonia, particularly in resource-limited settings where anti-Xa monitoring is unavailable.</p>