Plaque rupture (PR) and superimposed thrombosis have been shown as the most frequent underlying substrate in acute coronary syndromes (ACS). Coronary angiography is a luminogram not able to define in vivo features of the culprit plaques. The aim of the study was to use optical coherence tomography (OCT) to investigate the pathology underlying complex (CL) and non-complex angiographic lesions (NCL). We retrospectively enrolled 107 ACS patients admitted to our institution; 83 with non-ST elevation ACS (NSTE-ACS) and 24 with ST-elevation myocardial infarction. Coronary angiography was performed and culprit lesions were classified according to Ambrose criteria into NCL (n = 47) and CL (n = 60). OCT imaging was then performed to better identify plaque morphology; either PR or intact fibrous cap, the presence of superimposed thrombosis, lipid rich plaque, and thin cap fibroatheroma (TCFA). OCT analysis showed that 58 lesions (54.2%) were classified as PR and 48 lesions (44.9%) were associated with thrombi. Lipid rich plaques were identified in 62 lesions (57.9%). PR, intracoronary thrombi, lipid rich plaques and TCFA were more frequent in CL compared with NCL (71.7 vs 31.9%, 63.3 vs 21.3%, 71.7 vs 40.4% and 46.7 vs 21.3% respectively), but PR with superimposed thrombus may be also detected in NCL. OCT demonstrates PR and thrombosis in the majority of ACS patients presenting with CL. However, one-third of NCL show PR by OCT, suggesting that additional intracoronary imaging by OCT may better identify the underlying mechanism of coronary instability than coronary angiography alone.