Compositional changes (alloying) in metals, ceramics and semiconductors lead to changes in microstructure and mechanical properties that range from subtle to dramatic. In particular, hardness measurements have been widely used to track changes in mechanical properties as a function of composition. In this study, composition dependence of the Vickers indentation hardness, H, is examined for 17 specimens that include 15 different n-type compositions within the quaternary chalcogenide family of LAST (lead-antimony-silver-tellurium) high-temperature thermoelectric materials. In addition, nanoindentation measurements were made on six of the 17 specimens that were indented via Vickers indentation. The H values obtained independently by the microindentation (Vickers indentation) and nanoindentation techniques agreed very well. In this study, relationships from the literature for the parabolic dependence of H on the single compositional variable x for pseudo binaries AB1−xCx is successfully extended to describe the composition dependence of H for a true quaternary system. Possible implications of hardness change on fabrication and in-service reliability are also discussed.