During the third trimester of pregnancy there is an increase in serum triglyceride and cholesterol levels. The mechanisms accounting for these changes in lipid metabolism during pregnancy are unknown. We hypothesized that during pregnancy the expression of nuclear hormone receptors involved in regulating lipid metabolism would be decreased. In 19 day pregnant mice, serum triglyceride and non-HDL cholesterol levels were significantly increased, while total cholesterol was slightly decreased, due to a decrease in the HDL fraction. Levels for mRNA of peroxisome proliferator activated receptor (PPAR), PPARB/ and PPAR, liver X receptor (LXR) and LXRB, farnesoid X receptor (FXR), and retinoid X receptor (RXR), RXRB, and RXR were significantly decreased in the livers of 19 day pregnant mice. Additionally the expression of thyroid receptor (TR), pregnane X receptor, SREBP-1a, SREBP1-c, SREBP-2,and liver receptor homologue 1, was also decreased while the expression of TRB, constitutive androstane receptor and hepatic nuclear factor 4 showed no significant change. mRNA levels of the PPAR target genes carnitine palmitoyl transferase I and acyl-CoA oxidase, the LXR target genes SERBP1c, ATP-binding cassette (ABC)G5 and ABCG8, the FXR target gene SHP, and the TR target genes malic enzyme and Spot 14 were all significantly decreased. Finally, the expression of PPAR co-activator (PGC)1 and PGC1B, known activators of a number of nuclear hormone receptors, was also significantly decreased. The decreases in expression of RXRs, PPARs, LXRs, FXR, TRs, SREBPs, and PGC1s could be one mechanism that leads to the alterations in lipid metabolism during late pregnancy.