We examined the effects of two over-the-counter H1-antihistamines on the progression of fatty liver disease in male C57Bl/6 wild-type and ApoE-/- mice. Mice were fed a high-fat diet (HFD) for 3 months, together with administration of either cetirizine (4 mg/kg b.w.) or fexofenadine (40 mg/kg b.w.) in drinking water. Antihistamine treatments increased body weight gain, gonadal fat deposition, liver weight and hepatic steatosis in wild-type mice, but not in ApoE-/- mice. Lobular inflammation, acute inflammation and necrosis were not affected by H1-antihistamines in either genotype. Serum biomarkers of liver injury tended to increase in antihistamine-treated wild-type mice. Serum level of glucose was increased by fexofenadine, while lipase was increased by cetirizine. H1-antihistamines reduced the mRNA expression of ApoE and carbohydrate response element binding protein (ChREBP) in wild-type mice, without altering the mRNA expression of sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FAS), or ApoB100, in either genotype. Fexofenadine increased triglycerides, while cetirizine increased cholesterol ester in liver, with a concomitant decrease in serum triglycerides by both antihistamines in wild-type mice. Antihistamines increased hepatic levels of conjugated bile acids in wild type mice, with the effect being significant in fexofenadine-treated animals. The increase was associated with changes in the expression of organic anion transport polypeptide 1b2 (Oatp1b2) and bile salt export pump (Bsep). These results suggest that H1-antihistamines increase the progression of fatty liver disease on wild-type mice, and there seems to be an association between the severity of disease, presence of ApoE and increase in hepatic bile acid levels.