AbstractMetal chalcogenides have attracted great attention because of their broad applications. It has been well acknowledged that microstructure can alter the intrinsic properties and performance of metal chalcogenides. The structure–property–performance relationships can be investigated at atomic scale with scanning transmission and transmission electron microscopy (STEM and TEM). Nevertheless, careful specimen preparation is paramount for accurate analyses and interpretations. In this work, we compare the effects of a variety of well-established TEM specimen preparation methods on the observed microstructure of an ingot stoichiometric lead telluride (PbTe). Most importantly, from aberration corrected STEM and first principles calculations, we discovered that argon (Ar) ion milling can lead to surface irradiation damage in the form of Pb vacancy clusters and self-interstitial atom (SIA) clusters. The SIA clusters appear as orthogonal nanoscale features when characterized along the <001> crystal orientation of the rock salt structured PbTe. This obfuscates the interpretation of the intrinsic microstructure of metal chalcogenides, especially lead chalcogenides. We demonstrate that with sufficiently low energy (300 eV) Ar ion cleaning or appropriate high-temperature annealing, the surface damage layer can be properly cleaned and the orthogonal nanoscale features are significantly reduced. This reveals the materials’ intrinsic structure and can be used as the standard protocol for future TEM specimen preparation of lead-based chalcogenide materials.