AbstractCis‐ and trans‐1,4‐dimethyl‐1‐d3‐methoxymethyl‐4‐(2‐methoxy‐2‐propyl)cyclohexane (3a‐c and 3a‐t), the isomeric 1,4‐dimethyl‐1‐methoxymethyl‐4‐(2‐d3‐methoxy‐2‐propyl)cyclohexanes (3b‐c and 3b‐t) and 1,4‐dimethyl‐1‐methoxymethyl‐4‐(2‐d3‐methoxy‐2‐propyl)cyclohexanes (3b‐c and 3b‐t) and 1,4‐dimethyl‐1‐ethoxymethyl‐4‐(2‐methoxy‐2‐propyl)cyclohexanes (3c‐c and 3c‐t) give rise to different isobutane chemical ionization (CI) mass spectra. The cis isomers exhibit abundant [MHROH]+ ions (100%, ROH originating from the tertiary alkoxy group), while no MH+ or [MHR′OH]+ ions (R′OH originating from the primary alkoxyl) were detected in the mass spectra. This behaviour indicates an efficient proton transfer between the two ether functions in the transient MH+ ions of the cis isomers, resulting in the total and exclusive elimination of methanol from the tertiary position. In contrast to the cis diethers, the trans isomers 3a‐t, 3b‐t and 3c‐t afford relatively abundant [MHROH]+ and [MHR′OH]+ ions. This behaviour is consistent with protonation on each of the two distant non‐interacting ether groups, resulting in two isomeric MH+ ions, each of which eliminates the corresponding alcohol. The highly stereospecific behaviour of the cis and trans diethers 3c and 3t is dependent on the presence of the methyl substituents at positions 1 and 4: identical mass spectra were obtained for cis‐ and trans‐1‐ alkoxymethyl‐4‐(2‐alkoxy‐2‐propyl)cyclohexanes (4‐c and 4‐t) (four pairs with different 1‐ and 4‐alkoxy groups), and both stereoisomers exhibit exclusive elimination of ROH originating from the tertiary methoxy group in each pair. The absence of [MHR′OH]+ and MH+ ions in the isobutane CI mass spectra of 4‐t requires proton transfer from the primary OR′ to the tertiary OR group prior to the elimination of ROH, despite the large distance between them in the trans configuration. These results indicate isomerization of the fragmenting MH+ ions of 4‐t to structures which allow a facile proton transfer from the primary the tertiary alkoxyl. The similarity of the mass spectra of 4‐c and 4‐t suggests trans → cis isomerization, which may occur via an ion–neutral complex.