The effect of systemic inflammation, represented by high-sensitivity C-reactive protein (hsCRP), on triglyceride glucose (TyG) index-associated cardiovascular risk in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) has not yet been determined. This study was a retrospective analysis of a single-center prospective registry and finally included 1701 patients (age, 60 ± 10 years; male, 76.7%). The primary endpoint was defined as major adverse cardiovascular events (MACE), including cardiovascular mortality, non-fatal stroke, and non-fatal myocardial infarction. In the multivariate COX regression model that included the GRACE risk score, higher TyG index was significantly associated with a greater incidence of MACE in patients with hsCRP levels less than 2 mg/L but not 2 mg/L or more (P for interaction = 0.039). Each unit increase in the TyG index was independently associated with a 52% increased risk of MACE only in patients with hsCRP levels less than 2 mg/L (P = 0.021). After adjustment for other confounding factors, including the GRACE risk score, compared with those in the group of TyG index < 8.62 and hsCRP < 2 mg/L, patients in the group of TyG index ≥ 8.62 and hsCRP ≥ 2 mg/L had a 3.9 times higher hazard ratio for developing MACE. The addition of both TyG index and hsCRP had an incremental effect on the predictive ability of the GRACE risk score-based prognostic model for MACE (C-statistic: increased from 0.631 to 0.661; cNRI: 0.146, P = 0.012; IDI: 0.009, P < 0.001). In conclusion, there was a significant interaction between the TyG index and hsCRP for the risk of MACE, and the TyG index was reliably and independently associated with MACE only when hsCRP levels were less than 2 mg/L. Furthermore, high TyG index and high hsCRP levels synergistically increased the risk of MACE, suggesting that the prognostic value of TyG index combined with hsCRP might be promising in patients with ACS undergoing PCI.