The use of electronic cigarettes (e-cigs) has surged in the past 20 years. These devices heat e-liquid containing nicotine and flavor additives into an aerosol form. While studies suggest flavors increase e-cigs use, neurobiological mechanism behind this remain understudied. Therefore, this study aims to understand the neurobiological substrate involved in the rewarding properties of inhaled flavored nicotine. We developed a nicotine-vaping induced conditioned place preference (CPP) protocol to test the rewarding effect of nicotine and flavors in a mouse model. In males, flavored nicotine dose-dependently increases CPP and decreases conditioned response variability. In females, increasing nicotine doses induce significant conditioned place aversion, which is prevented by the addition of flavors. Sex differences in behavioral response were supported by differences in nicotine metabolism. A large-scale c-fos analysis targeting key brain regions was then performed. Following exposure to flavored nicotine, increased c-fos expression was observed in the medial olfactory tubercle (mOT), but not in the nucleus accumbens (Nacc). The mOT is indeed directly connected to both the ventral tegmental area (VTA) and the posterior olfactory bulb (pOB), supporting its role in olfactory reward. Several brain structures involved in olfaction, reward, and aversion are currently under analysis to identify network activations. Moreover, dynamic changes in the mOT during exposure to flavored nicotine are under investigation using fiber photometry. Altogether, these findings will help to elucidate the role of the mOT in processing olfactory reward, which is essential to further understand neural circuits involved in reinforcing effects of flavors in e-cigs.