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Purpose: To compare dermal regenerative template (DRT), with and without split-thickness skin-grafting (STSG), and urinary bladder matrix (UBM) for coverage of lower extremity wounds. Methods: A retrospective review of 56 lower extremity wounds treated with either DRT and STSG (DRT-S) (n = 18), DRT only (n = 17), or UBM only (n = 21). Patient characteristics, comorbidities, American Society of Anesthesiology (ASA) classification, injury characteristics, wound characteristics, use of negative pressure wound therapy, surgical details, postoperative care, and failure of primary wound coverage procedure were documented. Results: The DRT group, compared to the DRT-S group, was older [median difference (MD) 17.4 years, 95% confidence interval (CI) 9.1–25.7; p = 0.0008], more diabetic (proportional difference (PD) 54.2%, CI 21.2–76.1%; p = 0.002), had smaller wounds (MD − 91.0 cm2, CI − 125.0 to − 38.0; p = 0.0008), more infected wounds (PD 49.0%, CI 16.1–71.7%; p = 0.009), a shorter length of stay after coverage (MD − 5.0 days, CI − 29.0 to − 1.0; p = 0.005), and no difference in primary wound coverage failure (41.2% vs. 55.6%; p = 0.50). The UBM group, compared to the DRT group, was younger (MD − 6.8 years; CI − 13.5 to − 0.1; p = 0.04), had fewer patients with an ASA > 2 (PD − 35.0%, CI − 55.2% to − 7.0%; p = 0.02), diabetes (PD − 49.2%, CI − 72.4% to − 17.6%; p = 0.003), and had no difference in primary wound coverage failure (36.4% vs. 41.2%; p = 1.0). Failure of primary wound coverage was found to only be associated with larger wound surface areas (MD 22.0 cm2, CI 4.0–90.0; p = 0.01). Conclusions: DRT and UBM coverage had similar rates of primary wound coverage failure for lower extremity wounds. Level of evidence: Diagnostic, Level III. [ABSTRACT FROM AUTHOR]