The influence of substitution of an <i>N,N,O</i>-trisubstituted hydroxylamine (-NR-OR'-) unit for a hydrocarbon (-CHR-CH<sub>2</sub>-), ether (-CHR-OR'-), or amine (-NR-CHR'-) moiety on lipophilicity and other ADME parameters is described. A matched molecular pair analysis was conducted across five series of compounds, which showed that the replacement of carbon-carbon bonds by <i>N,N,O</i>-trisubstituted hydroxylamines typically leads to a reduction in log<i>P</i> comparable to that achieved with a tertiary amine group. In contrast, the weakly basic <i>N,N,O</i>-trisubstituted hydroxylamines have greater log<i>D</i> <sub>7.4</sub> values than tertiary amines. It is also demonstrated that the <i>N,N,O</i>-trisubstituted hydroxylamine moiety can improve metabolic stability and reduce human plasma protein binding relative to the corresponding hydrocarbon and ether units. Coupled with recent synthetic methods for hydroxylamine assembly by N-O bond formation, these results provide support for the re-evaluation of the <i>N,N,O</i>-trisubstituted hydroxylamine moiety in small-molecule optimization schemes in medicinal chemistry.