OBJECTIVE Part of platelet function involves aggregation and activation. Activation leads to platelet P selectin expression and platelet-leukocyte aggregation. Hypertonic saline inhibits platelet aggregation, although the effects of hypertonic saline on platelet activation are not known. We evaluated the effects of hypertonic saline on platelet activation as measured by platelet P selectin expression and platelet-leukocyte aggregation. METHODS Blood samples from healthy volunteers (n = 6) were treated in vitro with various solutions including 23.5%, 7.5%, 3%, and 0.9% saline; Ringer's solution; 5% dextrose in water; and 10% hydroxyethyl starch. Blood was diluted with each type of solution to 2.5%, 5%, 10%, 20%, and 30% (vol/vol) dilution. All blood samples were activated with adenosine diphosphate (20 micromol/L), stained with fluorochrome-conjugated antibodies, and analyzed by flow cytometry to measure platelet P selectin expression and platelet-leukocyte aggregation. RESULTS The 23.5% saline solution reduced P selectin expression at 20% and 30% dilutions and platelet-leukocyte aggregation at 10%, 20%, and 30% dilutions. The 7.5% solution saline had no effect on P selectin expression and significantly inhibited platelet-leukocyte aggregation only at 30% dilution. Other solutions had no effect on platelet P selectin expression or platelet-leukocyte aggregation. CONCLUSIONS Our data suggest that hypertonic saline does not affect platelet P selectin expression or platelet-leukocyte aggregation at therapeutic plasma concentrations but that an inhibitory effect occurs at supratherapeutic doses. Dilutions of other solutions caused the least disturbance of platelet activation.