This study aimed to investigate the impact of high-sensitivity C-reactive protein (hsCRP) on Lipoprotein(a) [Lp(a)] associated cardiovascular risk in patients with ST-segment elevation myocardial infarction (STEMI) underwent percutaneous coronary intervention (PCI). A total of 2318 STEMI-PCI patients were retrospectively recruited, and further stratified based on postprocedural hsCRP levels (≥ 2 vs < 2 mg/L). Major adverse cardiac events (MACE) were defined as all-cause death, myocardial infarction and stroke. During a mean follow-up of 2.5 years, MACE occurred in 159 (6.9%) patients. In the setting of hsCRP ≥ 2mg/L, per unit increase of Lp(a) was associated with a 28% increase of MACE risk (HR: 1.28, 95% CI: 1.09 to 1.49, p = 0.002; p = 0.031 for interaction); increasing tertiles of Lp(a) were significantly related to greater rates of MACE (p = 0.011 for interaction; p = 0.005 for trend across tertiles). Patients with upper tertile of Lp(a) had a significant lower event-free survival (p = 0.034) when hsCRP ≥ 2mg/L. No similar association between Lp(a) and MACE was noted when hsCRP < 2mg/L. In conclusion, high Lp(a) levels were associated with poor prognosis when hsCRP ≥ 2mg/L, implying systemic inflammation can modulate Lp(a)-associated MACE risk in STEMI-PCI patients. Measurement of Lp(a) in patients with high inflammation risk may identify individuals at high cardiovascular risk.