OBJECTIVE To evaluate the efficacy of fixed combination brimonidine-timolol (FCBT) in comparison with brimonidine tartrate 0.2% and control for the treatment of intraocular pressure (IOP) spikes after neodymium:YAG (Nd:YAG) laser posterior capsulotomy. METHODS One hundred five eyes of 105 patients were enrolled in the study. Patients were randomized to 3 groups (each group, including 35 patients): the FCBT group that received 1 drop of FCBT, the brimonidine group that received 1 drop of brimonidine tartrate 0.2%, and the control group that received 1 drop of artificial tear, 1 h before the laser procedure. Postoperative IOP measurements were performed at 1st, 2nd, 3rd, 24th hours, and seventh day. RESULTS The mean IOP changes from baseline were statistically different between the study groups at first, second, and third hours (all P<0.001). Pairwise comparisons showed that although the mean IOP changes of the treatment groups were similar at 1st and 24th hours and seventh day (all P>0.05), the IOP levels of the brimonidine group were less reduced from baseline than the FCBT group at second and third hours (P=0.01 and P=0.03, respectively). The differences among the study groups concerning the incidence of IOP elevations of ≥5 or ≥10 mmHg were statistically significant (P=0.007, P=0.04, respectively). However, the differences between the treatment groups were not statistically significant (both P>0.05). CONCLUSIONS This study has shown that preoperative instillation of 1-drop FCBT was safe and effective for preventing IOP spikes after Nd:YAG laser posterior capsulotomy. FCBT may be a better option than brimonidine tartrate 0.2%, which is one of the current standard prophylaxes for these spikes.