The effects of the CF<sub>2</sub>H moiety on H-bond (HB) acidity and lipophilicity of various compounds, when attached directly to an aromatic ring or to other functions like alkyls, ethers/thioethers, or electron-withdrawing groups, are discussed. It was found that the CF<sub>2</sub>H group acts as a HB donor with a strong dependence on the attached functional group ( A = 0.035-0.165). Regarding lipophilicity, the CF<sub>2</sub>H group may act as a more lipophilic bioisostere of OH but as a similar or less lipophilic bioisostere of SH and CH<sub>3</sub>, respectively, when attached to Ar or alkyl. In addition, the lipophilicity of ethers, sulfoxides, and sulfones is dramatically increased upon CH<sub>3</sub>/CF<sub>2</sub>H exchange at the α position. Interestingly, this exchange significantly affects not only the polarity and the volume of the solutes but also their HB-accepting ability, the main factors influencing log P<sub>oct</sub>. Accordingly, this study may be helpful in the rational design of drugs containing this moiety.