Background Plasma levels of angiopoietin‐2 (ANGPT2) and angiopoietin‐like 4 protein (ANGPTL4) reflect different pathophysiological aspects of cardiovascular disease. We evaluated their association with outcome in a hospitalized Norwegian patient cohort (n = 871) with suspected acute coronary syndrome (ACS) and validated our results in a similar Argentinean cohort (n = 982). Methods A cox regression model, adjusting for traditional cardiovascular risk factors, was fitted for ANGPT2 and ANGPTL4, respectively, with all‐cause mortality and cardiac death within 24 months and all‐cause mortality within 60 months as the dependent variables. Results At 24 months follow‐up, 138 (15.8%) of the Norwegian and 119 (12.1%) of the Argentinian cohort had died, of which 86 and 66 deaths, respectively, were classified as cardiac. At 60 months, a total of 259 (29.7%) and 173 (17.6%) patients, respectively, had died. ANGPT2 was independently associated with all‐cause mortality in both cohorts at 24 months hazard ratio (HR) 1.27 (95% confidence interval (CI), 1.08–1.50) for Norway, and HR 1.57 (95% CI, 1.27–1.95) for Argentina, with similar results at 60 months HR 1.19 (95% CI, 1.05–1.35) (Norway), and HR 1.56 (95% CI, 1.30–1.88) (Argentina), and was also significantly associated with cardiac death HR 1.51 (95% CI, 1.14–2.00), in the Argentinean population. ANGPTL4 was significantly associated with all‐cause mortality in the Argentinean cohort at 24 months HR 1.39 (95% CI, 1.15–1.68) and at 60 months HR 1.43 (95% CI, 1.23–1.67), enforcing trends in the Norwegian population. Conclusions ANGPT2 and ANGPTL4 were significantly associated with outcome in similar ACS patient cohorts recruited on two continents. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00521976. ClinicalTrials.gov Identifier: NCT01377402.