Perturbation molecular orbital analysis has been used for a computation of the through-bond and through-space orbital interactions of oxygen lone pairs in dimethoxymethane (DMM). The analysis predicts the symmetrical combination of p-type lone pairs as a highest occupied orbital in an antiperiplanar conformation. The conformational dependence of through-bond orbital interactions has the character of the V2 term in the Fourier expansion of the rotation potential function about the C—O bond. Contrary to the recent theoretical interpretation that the anomeric effect (preference of gauche conformation) is caused by superjacent orbital control, the orbital interactions in DMM are not dominant terms with respect to the anomeric or exoanomeric effect. The dipole–dipole interactions of the C—O bonds stabilizing the gauche conformation should thus be considered as the primary cause of the anomeric effect in DMM. The frontier orbital energies and geometric parameters in DMM are strongly influenced by a variation of orbital interaction with rotation. Results obtained for DMM are used to explain the conformational behaviour of other molecules containing the acetal moiety, such as pyrane heterocycles, sugars, and polyoxymethylene.