This study sought to determine the anatomic characteristics and clinical presentation associated with a calcified nodule (CN) as assessed by optical coherence tomography. CN is an unusual but demonstrable cause of acute coronary syndromes (ACS). We studied 889 de novo culprit lesions in 889 patients (48% ACS) who underwent optical coherence tomography before intervention. CN was defined as an eruptive accumulation of nodular calcification (small fractured calcifications). Using quantitative coronary angiography, the change in the angle of the lesion between diastole and systole was measured (angiographic Δ angle). CN was seen in 4.2% of all lesions and was located more frequently in the ostial or mid right coronary artery. Hemodialysis (odds ratio: 4.0; 95% confidence interval: 1.1 to 13.4; p = 0.04), in-lesion angiographic Δ angle (odds ratio: 1.09; 95% confidence interval: 1.05 to 1.14; p < 0.001), and maximum calcium arc by optical coherence tomography (odds ratio: 1.02; 95% confidence interval: 1.01 to 1.02; p < 0.001) were significantly associated with the presence of a CN in the multivariable model. When we compared CNs in patients with ACS versus stable angina presentation, there was a smaller minimum lumen area (1.04 mm2 first quartile, third quartile: 0.69, 1.26 vs. 1.61 first quartile, third quartile: 1.03, 2.06 mm2; p = 0.02) accompanied by more thrombus (82.4% vs. 20.0%; p < 0.001) in CN lesions with ACS presentation. In lesions with severe calcification (maximum calcium arc >180°), 30% of ACS culprit lesions contained a CN, and the presence of a CN was associated with ACS presentation independent of other vulnerable plaque morphologies. The presence of a CN was associated with severe calcification and larger hinge movement of the coronary artery (especially ostial and mid right coronary artery). One-third of the underlying plaque morphology of severely calcified culprit lesions in patients with ACS was caused by a CN. Display omitted