The preferred framework site for Si substitution by Al in the ETS-10 structure has been modeled by both lattice energy minimization (LEM) and semiempirical quantum chemical (QC) calculations on model clusters. Both approaches suggest that Al substitution in the ETS-10 structure will follow an Al, Ti avoidance rule, consistent with conclusions drawn from analysis of solid-state Si-29 and Al-27 NMR spectra of Al-substituted ETS-IO reported elsewhere. The Al-substituted ETS-IO structure (ETAS-IO) involving a Al-O-Si-O-Ti (T1) linkage was successfully minimized, showing only minor deviations from the optimized ETS-10 structure. In contrast, constant pressure minimizations of ETAS-10 substituted at T2 sites lead to the cleavage of the Ti-O-Al linkage. Indeed, QC calculations indicate that, compared to Al-O-Si-O-Ti Linkages, Al-O-Ti direct linkages result in enhanced electronic repulsion between neighboring negative charges on Al and Ti sites and higher lattice strains. This suggests that both electronic and strain factors are influencing the observed preferential Al siting.