The replacement of oxygenated functionality (hydroxy and alkoxy) with a fluorine atom is a commonly used bioisosteric replacement in medicinal chemistry. In this paper, we use molecular matched-pair analysis to better understand the effects of this replacement on lipophilicity. It seems that the reduced log P of the oxygenated compound is normally dominant in determining the size of this difference. We observe that the presence of additional electron-donating groups on an aromatic ring generally increases the difference in lipophilicity between an oxygenated compound and its fluorinated analogue, while electron-withdrawing groups lead to smaller differences. Ortho-substituted compounds generally display a reduced difference in log P compared to para- and meta-substituted compounds, particularly if an ortho-substituent can form an intramolecular hydrogen bond. Hydrogen-bond acceptors remote to an aromatic ring containing fluorine/oxygen can also reduce the difference in log P between oxygen- and fluorine-substituted compounds.