A novel series of substituted N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-N-(3-phenoxyphenyl)-trifluoro-3-amino-2-propanols is described which potently and reversibly inhibit cholesteryl ester transfer protein (CETP). Starting from the initial lead 1, various substituents were introduced into the 3-phenoxyaniline group to optimize the relative activity for inhibition of the CETP-mediated transfer of [3H]-cholesteryl ester from HDL donor particles to LDL acceptor particles either in buffer or in human serum. The better inhibitors in the buffer assay clustered among compounds in which the phenoxy group was substituted at the 3, 4, or 5 positions. In general, small lipophilic alkyl, haloalkyl, haloalkoxy, and halogen moieties increased potency relative to 1, while analogues containing electron-donating or hydrogen bond accepting groups exhibited lower potency. Compounds with polar or strong electron-withdrawing groups also displayed lower potency. Replacement of the phenoxy ring in 1 with either simple aliphatic or cycloalkyl ethers as well as basic heteroaryloxy groups led to reduced potency. From the better compounds, a representative series 4a-i was prepared as the chirally pure R(+) enantiomers, and from these, the 4-chloro-3-ethylphenoxy analogue was identified as a potent inhibitor of CETP activity in buffer (4a, IC50 0.77 nM, 59 nM in human serum). The simple R(+) enantiomer 4a represents the most potent acyclic CETP inhibitor reported. The chiral synthesis and biochemical characterization of 4a are reported along with its preliminary pharmacological assessment in animals.