We investigated the correlation between insulin resistance (IR) and optical coherence tomography and identified culprit plaque characteristics in patients with acute coronary syndrome (ACS). Patients with ACS who underwent selective coronary intervention were prospectively enrolled. A total of 159 culprit lesions were identified in 145 patients. Culprit plaque characteristics, including thin-cap fibroatheroma (TCFA) and spotty calcification, were analyzed. The IR was assessed using the homeostasis model assessment of IR (HOMA-IR). Patients were divided into 4 interquartile ranges (IQRs) according to HOMA-IR values. The prevalence rates of TCFA were significantly different among the 4 groups (17.5% [IQR1 group] vs 17.9% [IQR2 group] vs 35.0% [IQR3 group] vs 55.0% [IQR4 group]; P = .001). Minimal fibrous cap thickness was inversely correlated with HOMA-IR level (141.35 [56.28] mu m vs 142.82 [82.17] mu m vs 102.14 [36.52] mu m vs 96.00 [41.82] mu m; P < .001). Spotty calcification prevalence was also significantly different among the 4 groups (5.9% vs 17.6% vs 32.4% vs 44.1%; P < .001). Compared with the bottom quartile, patients with elevated HOMA-IR values had higher prevalence of macrophage infiltration (P < .001) and microvessels (P = .023). On multivariate analysis, Ln HOMA-IR (odds ratio: 6.022; 95% confidence interval: 3.007-12.060; P < .001) was the independent predictor for spotty calcification. The current study showed increased IR was independently associated with plaque vulnerability, spotty calcification in particular, in ACS.