Description: Background Current recommendations for lipoprotein(a) (Lp[a]) focus on the control of other risk factors, including lowering low-density lipoprotein cholesterol (LDL-C), with little evidence to support this approach. Identifying interactions between Lp(a) and other risk factors could identify individuals at increased risk for Lp(a)-mediated disease. Methods and Results We used a case-only study design and included 939 participants (median age=49 years, interquartile range 46–53, women=33.1%) from the GENdEr and Sex determInantS of cardiovascular disease: from bench to beyond-Premature Acute Coronary Syndrome (GENESIS-PRAXY) study, a multicenter prospective cohort study of premature acute coronary syndrome. There was a higher prevalence of elevated Lp(a) levels (〉50 mg/dL; 80th percentile) in PRAXY participants as compared to the general population (31% versus 20%; P 〈0.001). Lp(a) was strongly associated with LDL-C (adjusted β 0.17; P 〈0.001). Individuals with high Lp(a) were more likely to have LDL-C 〉2.5 mmol/L, indicating a synergistic interaction (adjusted odds ratio 1.51; 95% CI 1.08–2.09; P =0.015). The interaction with high Lp(a) was stronger at increasing LDL-C levels (LDL-C 〉3.5, adjusted odds ratio 1.87; LDL-C 〉4.5, adjusted odds ratio 2.72). In a polytomous logistic model comparing mutually exclusive LDL-C categories, the interaction with high Lp(a) became attenuated at LDL-C ≤3.5 mmol/L (odds ratio 1.16; 95% CI 0.80–1.68, P =0.447). Other risk factors were not associated with high Lp(a). Conclusions In young acute coronary syndrome patients, high Lp(a) is more prevalent than in the general population and is strongly associated with high LDL-C, suggesting that Lp(a) confers greater risk for acute coronary syndrome when LDL-C is elevated. Individuals with high Lp(a) and LDL-C 〉3.5 mmol/L may warrant aggressive LDL-C lowering.