Despite potent insulin-sensitizing, anti-inflammatory, and antiatherogenic effects in animal studies, the relationship between serum adiponectin level and coronary artery disease in patients remains unclear. We determined the adiponectin profile in a cohort of multiethnic Asian patients with coronary artery disease, and the association between serum adiponectin level and culprit lesion necrotic core (NC) content. Ninety-four Asian patients (BMI, 25.3 ± 3.7 kg/m2) undergoing percutaneous coronary intervention were recruited. The serum adiponectin level was measured (n = 94), and the baseline virtual histology intravascular ultrasound examination was analyzed (n = 88). The median level of adiponectin was 3.7 µg/ml (interquartile range, 2.8–4.5 µg/ml). The serum adiponectin level was below 10 µg/ml in 90 patients (95.7%) and below 6 µg/ml in 80 patients (85.1%). There was a significant association between ethnicity and serum adiponectin level (P = 0.048). The median adiponectin level was highest among the Chinese, followed by the Malay and the Indians. Serum adiponectin levels were positively associated with culprit lesion NC content. A 1-µg/ml increase in log adiponectin was associated with a 3.04% (95% confidence interval: 0.33–5.44) increase in culprit lesion NC content. This association remains significant after adjusting for age, sex, ethnicity, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and procedural indication. We found a low serum level of adiponectin in Asian patients and a significant ethnic effect on serum adiponectin level. Increased serum adiponectin levels were independently associated with increased culprit lesion NC burden, suggesting a role for adiponectin in modulating coronary plaque vulnerability.