A quantitative structure-property relationship (QSPR) was developed, aiming to estimate the gas-phase enthalpies of formation (Delta H-f(0)) of a set of 132 organometallic compounds of general formula MRnXn- m, where M is a metal or a semimetal from groups 12 to 16, R is an alkyl, aryl, alkenyl, or alkynyl group, and X is Cl, Br, I, or H. The proposed model, derived from multilinear regression, contains nine descriptors that can be readily calculated from molecular structures. Correlations with R-2 and RMSE of 0.988 (29.1) and 0.990 (30.2) for the training and prediction sets, respectively, are obtained. The ability of QSPR methods to estimate reliable values of enthalpies of formation has been confirmed by the results obtained with a set of 168 organic compounds, which contain the same type of groups of the organometallic compounds. The nine descriptors-derived model, containing only descriptors of the constitutional, topological, and geometrical types, predicts Delta H-f(0) with accuracies comparable to well established additive methods.