The effects of ocean acidification on fish are only partially understood. Studies on olfaction are mostly limited to behavioral alterations of coral reef fish; studies on temperate species and/or with economic importance are scarce. The current study evaluated the effects of short- and medium-term exposure to ocean acidification on the olfactory system of gilthead seabream (
Sparus aurata
), and attempted to explain observed differences in sensitivity by changes in the protonation state of amino acid odorants. Short-term exposure to elevated
P
CO
2
decreased olfactory sensitivity to some odorants, such as L-serine, L-leucine, L-arginine, L-glutamate, and conspecific intestinal fluid, but not to others, such as L-glutamine and conspecific bile fluid. Seabream were unable to compensate for high
P
CO
2
levels in the medium term; after 4 weeks exposure to high
P
CO
2
, the olfactory sensitivity remained lower in elevated
P
CO
2
water. The decrease in olfactory sensitivity in high
P
CO
2
water could be partly attributed to changes in the protonation state of the odorants and/or their receptor(s); we illustrate how protonation due to reduced pH causes changes in the charge distribution of odorant molecules, an essential component for ligand-receptor interaction. However, there are other mechanisms involved. At a histological level, the olfactory epithelium contained higher densities of mucus cells in fish kept in high CO
2
water, and a shift in pH of the mucus they produced to more neutral. These differences suggest a physiological response of the olfactory epithelium to lower pH and/or high CO
2
levels, but an inability to fully counteract the effects of acidification on olfactory sensitivity. Therefore, the current study provides evidence for a direct, medium term, global effect of ocean acidification on olfactory sensitivity in fish, and possibly other marine organisms, and suggests a partial explanatory mechanism.