Raloxifene hydrochloride (RLX) is a selective estrogen-receptor modulator for treatment of osteoporosis and prevention of breast and endometrial cancer. By virtue of extensive presystemic clearance, RLX bioavailability is only 2%. The current study aimed to tailor and characterize RLX-loaded self-nanoemulsifying drug-delivery systems (SNEDDS) using bioactive excipients affecting drug metabolism. The potential of oral nanocarriers to enhance RLX delivery to endocrine target organs was assessed in fasted and fed female Wistar rats using high-performance liquid chromatography. RLX was loaded in the dissolved and dispersed status in the alkalinized (A-SNEDDS) and nonalkalinized (NA-SNEDDS) systems, respectively. Optimization and assessment relied on solubility studies, emulsification efficiency, phase diagrams, dilution robustness, cloud point, particle size, zeta potential (ZP), polydispersity index (PDI), and transmission electron microscopy. In vitro release was assessed using dialysis bag versus dissolution cup methods. NA-SNEDDS were developed with suitable globule size (38.49 ± 4.30 nm), ZP (31.70 ± 3.58 mV), PDI (0.31 ± 0.02), and cloud point (85°C). A-SNEDDS exhibited good globule size (35 ± 2.80 nm), adequate PDI (0.28 ± 0.06), and lower ZP magnitude (-21.20 ± 3.46 mV). Transmission electron microscopy revealed spherical globules and contended data of size analysis. Release studies demonstrated a nonsignificant enhancement of RLX release from NA-SNEDDS compared to drug suspension with the lowest release shown by A-SNEDDS. A conflicting result was elucidated from in vivo trial. A significant enhancement in RLX uptake by endocrine organs was observed after nanocarrier administration compared to RLX suspension. In vivo studies reflected a poor in vitro/in vivo correlation, recommended nanocarrier administration before meals, and did not reveal any advantage for drug loading in the solubilized form (A-SNEDDS). To conclude, NA-SNEDDS possessed superior in vitro characteristics to A-SNEDDS, with equal in vivo potential. NA-SNEDDS elaborated in this work could successfully double RLX delivery to endocrine target organs, with promising consequences of lower dose and side effects of the drug. © 2012 Elsheikh et al, publisher and licensee Dove Medical Press Ltd.