Uridine 5'-hexadecylphosphate (UMPC16) inhibited the growth of Saceharomyces cerevisiae under a hypersaline stress condition with Na+ more strongly than the calcineurin inhibitor cyclosporine A (CsA). Additional Ca2+ supplementation similarly suppressed the inhibitory activities of UMPC16 and CsA on yeast cell growth in a medium with Na+. UMPC16, but not CsA, accelerated mitochondrial reactive oxygen species (ROS) generation in combination with Na', suggesting its inhibition of a Ca2+-dependent but calcineurin-independent mechanism for protection against Na+ toxicity.