Sexual dimorphism in mammalian liver impacts genes affecting hepatic physiology, including inflammatory responses, diseased states and the metabolism of steroids and foreign compounds. Liver sex-specificity is dictated by sex differences in pituitary growth hormone (GH) secretion, with the transcription factor STAT5b required for intracellular signaling initiated by the pulsatile, male plasma GH profile. STAT5a, a minor liver STAT5 form >90% identical to STAT5b, also responds to sexually dimorphic plasma GH stimulation, but is unable to compensate for the loss of STAT5b and the associated loss of sex-specific liver gene expression. A large-scale gene expression study was conducted using 23,574-feature oligonucleotide microarrays and livers of male and female mice, both wild-type and Stat5a-inactivated, to elucidate any dependence of liver gene expression on STAT5a. Significant sex differences in expression were found for 2482 mouse genes, 1045 showing higher expression in males and 1437 showing higher expression in females. In contrast to the widespread effects of the loss of STAT5b, STAT5a deficiency had a limited but well defined impact on liver sex-specificity, with 219 of 1437 female-predominant genes (15%) specifically decreased in expression in STAT5a-deficient female liver. Analysis of liver RNAs from wild-type mice representing three mixed strains identified 1028 sexually dimorphic genes across the strains, including 393 female-predominant genes, of which 89 (23%) required STAT5a for normal expression in female liver. These findings highlight the importance of STAT5a for regulation of sex-specific gene expression specifically in female liver, in striking contrast to STAT5b, whose major effects are restricted to male liver.