The conformation and the electronic structure of several α-heterosubstituted acetone oximes XCH2(CH3)CNOH (X = H (1), F (2), Cl (3), CH3O (4), C2H5S (5), and (CH3)2N (6)) have been determined by means of a multidisciplinary approach based on ultraviolet photoelectron (UP), electron transmission (ET), and dissociative electron attachment (DEA) spectroscopies and fully optimized ab initio 6-31G** and MP2/6-31G** calculations. The vertical ionization energy (IE) and electron affinity (EA) values related to the HOMO (πC  N) and LUMO (π*C  N) have been determined by the ΔSCF and ΔMP2 (IE only) procedures. The compounds studied prefer an anti (E) configuration between the OH and the CH2X group and a gauche conformation of the C−X bond with respect to the double bond, except 2 and 4 for which a syn (Z) planar structure is nearly degenerate with the E one. The spectral data, coupled with the results of the calculations, indicate that the properties of the acetone oximes are mainly governed by the mixing between the orbitals localized at the X and CN fragments and by electrostatic interactions between hydrogen and the electronegative atoms. When X has poor donor and poor mesomeric acceptor properties (X = F and OMe), the prevailing interaction is the strong charge-transfer mixing of the hydroxyl oxygen lone pair with the π*C  N orbital and the X group moves in the main molecular plane.