Background Although patients with a cancer history have a 2 to 3 times higher risk for acute coronary syndrome (ACS), the morphological characteristics of ACS culprit plaque in those patients and their relations with clinical outcomes remain unknown. Methods and Results This retrospective, multicenter, observational cohort study included consecutive patients with ACS who underwent optical coherence tomography-guided emergent percutaneous coronary intervention. Patients were categorized into those without a cancer history, those with a cancer history, and those currently receiving cancer treatment. ACS culprit lesions were classified as plaque rupture, plaque erosion, or calcified nodule using optical coherence tomography. Plaque erosion frequency was significantly higher in culprit lesions of patients with current cancer and patients with cancer history than in those of patients without cancer history (56.3% versus 61.7% versus 36.5%). Calcified nodule incidence was significantly higher in patients without cancer history than in patients with current cancer and patients without cancer history (patients with current cancer: 12.4% versus patients without cancer history: 25.5% versus patients without cancer history: 12.6%, P<0.001). Cancer history was independently associated with nonplaque rupture (plaque erosion or calcified nodule) in ACS culprit lesions (odds ratio, 4.00; P<0.001). Cancer history was independently associated with major adverse cardiovascular events (hazard ratio [HR], 1.98; P=0.002). Nonplaque rupture in ACS culprit lesions was independently associated with major adverse cardiovascular events (HR, 1.60; P=0.011). Conclusions Patients with a cancer history had significantly worse clinical outcomes after ACS than those without a cancer history. Those with a cancer history had significantly higher plaque erosion and calcified nodule incidences in the ACS culprit lesions, which might partly explain their worse clinical outcomes. Registration URL: www.umin.ac.jp/ctr/index.htm. Unique Identifier: UMIN000038442.