To determine the optimum solution concentration for lowering elevated tear film osmolarity in keratoconjunctivitis sicca (KCS), tear osmolarity was measured in four KCS patients before and after instillation of either an isotonic saline solution or one of four hypotonic saline solutions (range, 75-225 mOsm/L). Average tear osmolarity one minute after instillation was significantly lower with the hypotonic solutions than with the isotonic saline (mean +/- SEM, 290 +/- 3 mOsm/L vs. 317 +/- 1 mOsm/L, P less than 0.0005). Solutions 150 mOsm/L or less were most effective in lowering osmolarity; the 75 mOsm/L solution was occasionally associated with irritation. In 16 KCS patients, we then compared the therapeutic efficacy of the 150 mOsm/L solution with that of an otherwise identical isotonic solution in a two-week, double-masked, crossover study. The 150 mOsm/L solution was superior for symptom relief by nearly 2:1 (P = 0.01).