ZnS nanoarchitectures have been intensively investigated recently because of their applications in optoelectronics and adsorption capacity. The potential hazard of ZnS nanoarchitectures is not well known. In this study, we investigated the toxicity of ZnS nanoarchitectures on vascular endothelial cell (VEC) in vitro and in vivo. The results showed that ZnS could inhibit human umbilical vein endothelial cell (HUVEC) proliferation at 50 and 200 μg/mL. Endothelial nitric oxide synthase (eNOS) activity, nitric oxide (NO), and reactive oxygen species productions were increased, which was companied with the decrease in caveolin-1 level. The endothelium of the aortic root was damaged and the NO levels in serum were elevated in the mice treated with 5 or 10 mg/kg ZnS for 3 and 6 days, but the body could repair the damage. The data suggested that the high concentration of ZnS could induce dysfunction of VECs through decreasing caveolin-1 and elevation of the eNOS activity and thus present toxicity. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 755–768, 2015.