Purpose: To compare the long-term effects of two preservative-free 0.005% latanoprost ophthalmic solutions with different excipient compositions on intraocular pressure (IOP), conjunctival hyperemia, and subjective ocular discomfort. Methods: The medical records of patients newly diagnosed with normal tension glaucoma or primary open angle glaucoma who started treatment using Xalost S® or Monoprost® were reviewed. IOP was measured with Goldmann applanation tonometry. Conjunctival hyperemia was measured with a Keratograph® 5M and subjective ocular discomfort was surveyed using a visual analog scale. Routine examinations were scheduled 1 week and 1, 3, 6, and 12 months after treatment. A generalized estimating equation was used to evaluate the changes of these parameters with time. Results: Xalost S® was used in 31 patients (60 eyes) and Monoprost® in 27 patients (50 eyes). The baseline characteristics were generally similar in the two groups with no significant differences. In the Xalost S® group, the IOP difference from baseline was significant at all time points (p < 0.001). However, in the Monoprost® group, after 1 month of treatment, the IOP difference decreased significantly (p = 0.054 at 1 week; p = 0.005 at 1 month; p < 0.001 after 1 month). Conjunctival hyperemia and subjective ocular discomfort did not differ significantly from baseline in either group. Conclusions There was no significant difference in the frequency of side effects between the two drugs. The effect on the IOP drop was similar over time, but the initial IOP drop was greater in the Xalost S® group. This difference is presumed to be due to the different excipient compositions of the two drugs.