To investigate the effect of dorzolamide hydrochloride on central corneal thickness in humans with cornea guttata. Randomized, placebo-controlled, double-masked, 2-drug crossover study with 10 patients with cornea guttata and 10 healthy controls, who had mean endothelial cell counts of 988 and 2377 cells/mm(2), respectively. Study medications were 2% dorzolamide and placebo drops applied 3 times a day for 4 weeks. Central corneal thickness measurements using ACMaster (Carl Zeiss Meditec AG, Jena, Germany) and Goldmann applanation tonometry were performed at baseline, 1 day, 1 week, and 4 weeks. The mean increases in central corneal thickness after 4 weeks in eyes with cornea guttata treated with dorzolamide and placebo were 26.3 microm (95% confidence interval, 8.8 to 43.7) and 3.3 microm (95% confidence interval, -0.5 to 7.1), respectively. No statistically significant changes were measured in the healthy control group. Dorzolamide caused a significant decrease in intraocular pressure (P < .01) while placebo did not cause significant changes (P = .50). Application of dorzolamide for 4 weeks resulted in a statistically significant increase in central corneal thickness in patients with compromised corneal endothelium. These results indicate that patients with corneal endothelial problems receiving dorzolamide therapy should be monitored.