Purpose: To investigate whether the brain-derived neurotrophic factor (BDNF) Val66Met genotype is associated with the rate of progression of open-angle glaucoma (OAG). Methods: In this retrospective cohort study, 148 OAG patients (292 eyes) were enrolled with a median follow-up period of 5.3 (range, 1.1-8.6) years. All participants had undergone regular clinical examinations by using spectral-domain optical coherence tomography (SD-OCT) scans and Humphrey (SITA) visual field tests. BDNF Val66Met polymorphisms were genotyped in all participants. Longitudinal visual field and retinal nerve fiber layer (RNFL) changes were compared between Met carriers (n = 68, 135 eyes) and Val homozygotes (n = 80, 157 eyes) by using the generalized estimating equations (GEE) model and Kaplan-Meier survival analysis. Results: There was no significant difference in mean rates of progression for the two genotypes. However, there was a significant association between the Val66Met genotypes and slower OAG progression, as suggested by a higher rate of global RNFL loss in Val/Val homozygotes (P = 0.008) in the long-term survival analysis. The effect demonstrated a degree of sex specificity, with the significant difference present only in females (P = 0.016) but not males. Similar sexual dimorphism was presented in superior (P = 0.005 in females, P = 0.38 in males) and inferior (P = 0.004 in females, P = 0.41 in males) RNFL loss. No significant difference was observed in visual field parameters. Conclusions: Our results suggested that carriage of Met allele reduces the rate of long-term OAG progression. However, the fact that this effect is observed only in females indicates BDNF Val66Met influences the progression rate of OAG in a sex-specific manner.