Purpose To evaluate the effect of topical prophylaxis with brinzolamide-brimonidine fixed combination on short-term intraocular pressure (IOP) elevation after intravitreal injections of anti-vascular endothelial growth factors (anti-VEGF). Methods This prospective comparative study included 56 eyes of 47 patients treated with intravitreal injections of anti-VEGF, and they were randomly divided into two groups. In control group (25 eyes), no prophylactic medication was used, whereas in case group (31 eyes) one drop of a fixed combination of brinzolamide-brimonidine was instilled two hours before the injection. IOP was measured before the injection and at 1 min, 10 min and 30 min post-injection in all eyes. Results The mean IOP before injection at 1 min, 10 min and 30 min post-injection was 16,6 +/- 2,8 mmHg, 53,4 +/- 12 mmHg, 26,4 +/- 5,5 mmHg and 17,9 +/- 4 mmHg, respectively, in control group and 15,1 +/- 3,4 mmHg, 42,6 +/- 8,4 mmHg, 21,4 +/- 5,5 mmHg and 12,4 +/- 3,5 mmHg, respectively, in case group. At 1 min, 10 min and 30 min post-injection, the mean IOP was significantly lower in case group compared with control group (p < 0,001, p = 0,0014 and p < 0,0001, respectively), but no difference at the pre-injection IOP between the two groups was found (p = 0,09). Conclusions The prophylactic administration of one drop of brinzolamide-brimonidine fixed combination significantly reduces the IOP spikes during the first 30 min after the intravitreal anti-VEGF injection.