The distribution and depletion profile of sulfadiazine (SDZ) were investigated in gilthead sea bream (Sparus aurata) fed on fish oil (FO) or plant oil-based (PO) diets. Fish averaging 230 g were given medicated feed containing 25 mg SDZ kg-1 fish for 5 days at 24-26oC. Blood and muscle plus skin were sampled on days 1, 3, 5, 6, 8 and 9. Differences in plasma and fillet SDZ levels between the two groups were statistically insignificant. The maximum drug concentrations in plasma were 3.2 ± 1.9 μg mL-1 and 2.9 ± 1.2 μg mL-1 in the PO and FO groups, respectively. In post-medicated samples depletion rapidly reached concentrations close to the level of quantification at 72 h post medication. Withdrawal times to reach consumer safety levels were calculated to be 103 and 118 h for the FO and the PO groups, respectively. N4-acetylation was found to be the major metabolic pathway of SDZ in gilthead sea bream fillet accounting for 23 and 19% of the parent compound in the FO and the PO groups, respectively. Overall, alteration of the dietary lipid profile induced insignificant effects on the kinetics of SDZ. The high tissue SDZ levels during medication and the fast removal of the parent compound and its metabolites from edible tissues of gilthead sea bream reflect a promising antibacterial profile.