Introduction: The incidence and nature of penetrating injuries differ between countries. The aim of this study was to analyze characteristics and clinical outcomes of patients with penetrating injuries treated at urban Level-1 trauma centers in the USA (USTC) and the Netherlands (NLTC). Methods: In this retrospective cohort study, 1331 adult patients (470 from five NLTC and 861 from three USTC) with truncal penetrating injuries admitted between July 2011 and December 2014 were included. In-hospital mortality was the primary outcome. Outcome comparisons were adjusted for differences in population characteristics in multivariable analyses. Results: In USTC, gunshot wound injuries (36.1 vs. 17.4%, p < 0.001) and assaults were more frequent (91.2 vs. 77.7%, p < 0.001). ISS was higher in USTC, but the Revised Trauma Score (RTS) was comparable. In-hospital mortality was similar (5.0 vs. 3.6% in NLTC, p = 0.25). The adjusted odds ratio for mortality in USTC compared to NLTC was 0.95 (95% confidence interval 0.35–2.54). Hospital stay length of stay was shorter in USTC (difference 0.17 days, 95% CI −0.29 to −0.05, p = 0.005), ICU admission rate was comparable (OR 0.96, 95% CI 0.71–1.31, p = 0.80), and ICU length of stay was longer in USTC (difference of 0.39 days, 95% CI 0.18–0.60, p < 0.0001). More USTC patients were discharged to home (86.9 vs. 80.6%, p < 0.001). Readmission rates were similar (5.6 vs. 3.8%, p = 0.17). Conclusion: Despite the higher incidence of penetrating trauma, particularly firearm-related injuries, and higher hospital volumes in the USTC compared to the NLTC, the in-hospital mortality was similar. In this study, outcome of care was not significantly influenced by differences in incidence of firearm-related injuries.