The main purpose of this study was to evaluate oral bioavailability of the poorly water-soluble drug fenofibrate when liposomes containing a bile salt were used as oral drug delivery systems. Liposomes composed of soybean phosphotidylcholine (SPC) and sodium deoxycholate (SDC) were prepared by a dry-film dispersing method coupled with sonication and homogenization. Several properties of the liposomes, including particle size, entrapment efficiency and membrane fluidity, were extensively characterized. In vitro release experiments indicated that no more than 20% of total fenofibrate was released from SPC/cholesterol (CL) and SPC/SDC liposomes at 2 h, in contrast with near complete release for micronized fenofibrate capsules. Strikingly, in vivo measurements of pharmacokinetics and bioavailability demonstrated higher rates of fenofibrate absorption from both SPC/SDC and SPC/CL liposomes than micronized fenofibrate. The bioavailability of SPC/SDC and SPC/CL liposomes was 5.13- and 3.28-fold higher, respectively, than that of the micronized fenofibrate. The disparity between oral bioavailability and in vitro release for liposomes strongly suggests alternative absorption mechanisms rather than enhanced release. Importantly, SPC/SDC liposomes exhibited a 1.57-fold increase in bioavailability relative to SPC/CL liposomes, indicating that liposomes containing bile salts may be used to enhance oral bioavailability of poorly water-soluble drugs.