Background: The triglyceride-glucose (TyG) index is a new alternative insulin resistance (IR) biomarker. The purpose of this study was to assess whether the TyG index can have a prognostic value in patients with acute coronary syndrome (ACS). Moreover, we wanted to compare the TyG index with HOMA index. Methods: We retrospectively enrolled 115 consecutive subjects, 81 males and 34 females, referred for ACS to our Unit of Cardiovascular Care of Policlinico Paolo Giaccone, Palermo. The subjects were divided into tertiles according to TyG index values and we performed a 3-year follow-up study. We considered as an end point new cardiovascular and cerebral events (MACCEs) during follow-up. Results: We found a significant statistical correlation between the HOMA index and the TyG index (p = 0.001). Patients with elevated TyG index have a higher incidence of MACCE at a 3-year follow-up. In our study the TyG index was an independent predictor of MACCEs (95% CI 1.8158 to 16.8068; P 0.0026) and the optimal TyG index cut-off for predicting MACCEs was 4.92 (sensitivity 76.56% and specificity 72.55%). Conclusions: The TyG index seems to significantly have an important prognostic role in patients with ACS and high values of TyG index are superior to HOMA-IR in predicting MACCEs.