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Summary Background Unfractionated heparin (UFH) is widely used to treat thromboembolic disease, but monitoring in children is challenging. Both activated partial thromboplastin time (aPTT) and anti-factor Xa activity (anti-Xa) are utilized, but a comparison of dosing nomograms has not been reported in pediatrics. Objective To compare the performance of aPTT and anti-Xa for UFH monitoring in pediatric patients. Design/methods A retrospective cohort study was conducted in patients ≤ 21 years old treated with UFH at Johns Hopkins Hospital from January 2009 to May 2011. For monitoring, an aPTT nomogram was used for the initial 15 months, and an anti-Xa nomogram was used for the subsequent 12 months. Clinical characteristics, laboratory data and outcomes were analyzed. Results Thirty-four patients were monitored with aPTT and 26 patients with anti-Xa. There was no significant difference in median time to therapeutic range (11.6 h aPTT, 95%CI = 6.0–17.0; 9.9 h anti-Xa, 95%CI = 7.3–20.7) or per cent of patients achieving therapeutic measurements at 24 (79% aPTT, 95%CI = 62–91; 73% anti-Xa, 95%CI = 52–88) and 48 h (88% aPTT, 95%CI = 73–97; 96% anti-Xa, 95%CI = 80–100). However, anti-Xa measurements were more frequently therapeutic than aPTT (74% [95%CI = 69–78] vs. 54% [95%CI = 50–59]). Variance between anti-Xa and aPTT measurements was high (R2 = 0.236). No significant difference was seen in bleeding incidence (9% aPTT, 95%CI = 2–24; 15% anti-Xa, 95%CI = 4–35). Conclusion The time to achieve therapeutic measures and bleeding outcomes were not significantly different between anti-Xa and aPTT nomograms. However, a small study size limits the power to detect clinically relevant differences. The results warrant larger prospective studies of UFH monitoring in children with thromboembolic disease.