Objectives: To assess and quantify coating irregularities on unexpanded and expanded durable polymer-based drug-eluting stents (DES) to gain insights into the origin of coating irregularities. Background: Previous scanning electron microscopy (SEM) studies in various expanded DES revealed differences in frequency and size of coating irregularities between DES types and specific distribution patterns, however, the origin of these irregularities is unclear. Methods: We assessed at bench side a total of 1,200 SEM images obtained in 30 DES samples (15 expanded and 15 unexpanded) of Cypher Select Plus, Taxus Liberté, Endeavor, Xience V, and resolute. Results: For most coating irregularities seen on expanded DES (72%; 23/32), a matching irregularity (n = 18/23) and/or its precursor (n = 11/23) was observed in unexpanded DES. Unexpanded Cypher select showed (small) crater lesions and cracks together with precursors of “peeling.” On unexpanded Taxus Liberté, thinning of polymer, small bare metal areas, wrinkles, and one precursor type were found. Unexpanded endeavor showed cracks, small bare metal areas, crater lesions, and precursors of the latter. Unexpanded Xience V and resolute mainly revealed crater lesions and their precursors. On unexpanded versus expanded DES, there was no difference in measured frequency of coating irregularities and precursors (P = ns) with the exception of more bare metal areas on expanded Taxus Liberte (P = 0.01). Conclusions: Most coating irregularities, or the potential to develop them, are inherent to the unexpanded DES. Important determinants of the formation of coating irregularities may be the stent geometry and the physical properties of the coating, while stent-balloon interaction plays no major role. © 2011 Wiley Periodicals, Inc.