As a result of their characteristic physical and optical properties, including their size, intense fluorescence, broad excitation, narrow emission and resistance to photobleaching, semiconductor nanocrystals are potentially useful for a variety of biological applications including molecular imaging, live-cell labeling, photodynamic therapy and targeted drug delivery. In this study, zinc sulfide (ZnS) semiconductor nanocrystals were synthesized in the 3 to 4 nm size range with selected capping agents intended to protect the nanocrystal core and increase its biological compatibility. We show that the biocompatibility of ZnS nanocrystals with primary murine splenocytes is influenced by the chemical structure of the outer capping agent on the nanocrystal. Additionally, the cytotoxicity of ZnS nanocrystals increases markedly as a function of time spent in suspension in phosphate-buffered saline (PBS). These data suggest that the potential therapeutic and/or biological use of ZnS nanocrystals is inherently dependent upon the proper choice of capping agent, as well as the conditions of nanocrystal preparation and storage. Copyright © 2012 John Wiley & Sons, Ltd.