Progesterone influences central neuronal excitability, a key event in migraine pathophysiology. Progesterone receptor gene (PGR) rs1042838 (G/T - Val660Leu) variant is indicative of PROGINS haplotype and associated to a reduced PGR activity. With the aim of investigating whether any type of association existed between this genetic variant and migraine pathophysiology, genotyping was performed in 380 consecutive migraine patients and 185 age-, sex-, and race-ethnicity-matched healthy controls from Interinstitutional Multidisciplinary BioBank (BioBIM) of IRCCS San Raffaele Pisana, Rome, Italy. rs1042838 genotypes did not correlate with demographics or clinical migraine features. However, TT (Leu) genotype was significantly associated with a later age of migraine onset: Patients affected by migraine with aura showed a linear relationship between copy number of the T allele carried by the individual and the age of migraine onset. Our data suggest that the PROGINS PGR polymorphism does not directly predispose to migraine but significantly delays migraine onset probably via a reduction in brain neuronal excitability.