OBJECTIVE We compared the systemic beta-adrenoceptor blockade elicited by metipranolol with timolol in a randomized, double-masked, multiple crossover study in 24 healthy volunteers. METHODS On each of 4 test days, subjects exercised on a treadmill for 10 min at 4 mi/h at a 5% gradient. After a 30-min rest, they received one drop OU of either 0.1 or 0.3% metipranolol HCI, 0.5% timolol maleate, or an artificial tear vehicle. RESULTS With 10 min of exercise, mean heart rate increased from +/-80 to 140 beats/min preinstillation. During the postinstillation exercise, mean heart rate increased to a maximum of 141.5 +/- 19.6, 141.8 +/- 17.2, 139.7 +/- 19.7, and 131.5 +/- 16.9 beats/min in the vehicle, 0.1% metipranolol, 0.3% metipranolol, and 0.5% timolol groups, respectively. Pairwise comparisons at this time revealed a significant difference between timolol and each of the other treatments. CONCLUSIONS Given the ocular hypotensive equivalency of various concentrations of metipranolol to timolol in other studies, it appears that metipranolol may have an improved therapeutic index relative to timolol.