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Males and females respond differently to drugs: indeed, sex plays a crucial role in determining drug pharmacokinetics and pharmacodynamics. Excipients have also been shown to enhance the biovailability of drugs differently in men and women. The aim of this work was to investigate whether rodents are a good model in which to study sex-specific effects of polyethylene glycol 400 (PEG 400) on the bioavailability of ranitidine. Ranitidine (50 mg/kg) was dissolved in water with different amounts of PEG 400–0 (control), 13, 26, 51, 77, 103, and 154 mg/kg; these solutions were dosed orally by gavage to male and female Wistar rats. Blood samples were withdrawn over 480 min and assayed via HPLC-UV. Individual ranitidine plasma profiles were constructed for each rat, and standard pharmacokinetic parameters were determined. In the male rats, the change in the area under the plasma ranitidine curve (AUC0–480) compared to the control group, was +18%; +49% (p < 0.05); +37% (p < 0.05); +31% (p < 0.05); +8% and −22% (p < 0.05) for PEG 400 doses of 13; 26; 51; 77; 103; and 154 mg/kg respectively. On the other hand, females showed no statistically significant difference between the groups. In conclusion, low doses of PEG 400 enhanced the bioavailability of ranitidine in male, but not female, rats. These findings are in agreement with previously published human data, therefore confirming the validity of the rodent model, and highlight the unusual and clinically significant phenomenon that an excipient can influence drug bioavailability in one gender and not the other.