The M06-2X/Def2-TZVP, B3PW91/Def2-TZVP, and B3LYP/LANL2DZ+dp levels of theory were used to investigate the effect of substituents on the stability of the triple-bonded RTl≡SbR molecule. For comparison, small groups (F, OH, H, CH3, and SiH3) and sterically bulky substituents, (Ar* (=C6H3-2,6-(C6H2-2,4,6-i-Pr3)2), Tbt (=C6H2-2,4,6-{CH(SiMe3)2}3), SiiPrDis2, and SiMe(SitBu3)2), were chosen for the present study. The density functional theory results indicate that the triple-bonded RTl≡SbR compounds with small ligands are transient intermediates, so their experimental detections should be extremely difficult. Nevertheless, the theoretical observations demonstrate that only the bulkier ligands can effectively stabilize the central Tl≡Sb triple bond. In addition, the valence-electron bonding model reveals that the bonding characters of the triple-bonded RTl≡SbR species possessing sterically bulky groups can be represented as RTl ← SbR. Nevertheless, on the basis of the natural resonance theory, the natural bond orbital, and the charge decomposition analysis, the theoretical observations suggest that the Tl≡Sb triple bond in the acetylene analogues, RTl≡SbR, should be very weak.