Soluble suppressor of tumorigenicity (sST)-2 plasma concentration is related to atherosclerosis. The aim of this study was to assess the prognostic impact of sST2 and its membrane-associated form (ST2L) in patients with carotid atherosclerotic plaque who underwent endarterectomy (CEA). Eighty-two consecutive patients (age range: 48–86 years) who underwent CEA were enrolled. Anthropometric, clinical, instrumental, and laboratory evaluations were gathered. Thirty-seven (45%) patients were symptomatic of cerebrovascular diseases. Patients underwent a five-year follow-up. Phone calls and the analysis of national and regional databases were performed in order to evaluate the occurrence of the primary outcome (all-cause mortality). The population was divided according to survival status. Statins were administered in 81% and 87.5% of survivors and non-survivors, respectively. sST2 levels were higher in non-survivors than in survivors (117.0 ± 103.9 vs. 38.0 ± 30.0 ng/mL, p < 0.001) and in symptomatic individuals, compared with asymptomatic (80.3 ± 92.1 ng/mL vs. 45.4 ± 41.4 ng/mL, p = 0.02). ROC curve analysis identified sST2 cut-off: >98.44 ng/mL as the best predictor for mortality. At the one-year follow-up, the survival rate decreased up to 20% in patients with sST2 higher than the cut-off value. A multivariate regression analysis revealed that only sST2 (HR: 1.012, 95% CI: 1.008–1.016, p < 0.0001) and triglycerides plasma levels (HR: 1.008, 95% CI: 1.002–1.015, p = 0.0135) remained significantly associated with all-cause mortality. ST2L was not associated with all-cause mortality risk. sST2 may act as an independent prognostic determinant of all-cause mortality and symptomatic cerebrovascular diseases in patients with carotid atherosclerotic plaque who underwent CEA.