Background <p>Little is known about the relationship between body mass index (BMI) and the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with acute coronary syndrome (ACS). This study aimed to investigate how BMI modifies the association between NT-proBNP levels and clinical outcomes in ACS patients.</p> Methods <p>A total of 11,757 ACS patients from the Cardiovascular Centre Beijing Friendship Hospital were recruited. The association between NT-proBNP and major adverse cardiovascular and cerebral events (MACCEs) was assessed using multivariate Cox proportional hazards models. The multiplicative interaction between NT-proBNP and BMI was evaluated using the Wald χ² test.</p> Results <p>During the median follow-up time of 3.04 (IQR: 1.07‒5.02) years (33,232 person-years), 1996 MACCEs were documented. A significant multiplicative interaction was observed between natural logarithm (Ln)-NT-proBNP and BMI (<i>p</i> for multiplicative interaction = 0.013). The categorical thresholds of NT-porBNP for the risk of MACCEs were 1559, 155, and 419 pg/ml for normoweight, overweight, and obese patients, respectively. When NT-proBNP levels were near-normal or mildly elevated (≤ 300 pg/ml), overweight and obese patients exhibited a higher event probability than normoweight patients at a given NT-proBNP level. However, an opposite trend was observed at significantly elevated NT-proBNP levels (&gt; 300 pg/ml), with normoweight patients showing a higher event probability. When BMI and NT-proBNP were considered jointly, normoweight patients with elevated NT-proBNP had a significantly higher risk of MACCEs than overweight patients without elevated NT-proBNP (hazard ratio: 2.28; 95% confidence interval: 1.83‒2.84; <i>p</i> &lt; 0.001).</p> Conclusion <p>The prognostic value of NT-proBNP in ACS patients varies with BMI, with the extent of NT-proBNP elevation playing a role in this relationship.</p>