Altered expression of neurotrophins may contribute to the pathogenesis of schizophrenia. Several studies suggest sex steroid hormones may be involved in the regulation of brain-derived neurotrophic factor (BDNF) signaling, as well as the symptoms of schizophrenia. This study aimed to identify sex differences in BDNF-TrkB signaling in the forebrain of wild type (WT) and BDNF heterozygous (+/-) mice. Protein expression of neurotrophins and TrkB were measured by Western blot analysis in brain regions pertinent to schizophrenia, namely the frontal cortex, striatum, and dorsal (DHP) and ventral hippocampus (VHP). In both the frontal cortex and striatum, protein expression levels of phosphorylated TrkB (pTrkB) over total TrkB (pTrkB/TrkB) was significantly increased in male, but not female BDNF(+/-) mice, suggesting sex-specific changes in TrkB signaling. pTrkB/TrkB levels were also elevated in the DHP of both male and female BDNF(+/-), while levels remained unchanged in the VHP, indicating region-specific changes in TrkB signaling. Sex-specific phosphorylation of TrkB corresponded with downstream changes in ERK2 phosphorylation in the frontal cortex and striatum. No sex-specific effects of genotype were found in the expression of TrkB ligands, BDNF and NT-4. However, a marked, region-specific increase in NT-4 expression was found in the striatum of both male and female BDNF(+/-) mice. In conclusion, there are complex sex- and region-specific changes in BDNF-TrkB signaling in BDNF(+/-) mice. These results provide new insight into sex-dependent BDNF signaling in forebrain regions and assist in understanding the role of neurotrophins in schizophrenia.