Applying chemical additives (molecule inhibitors or dispersants) is a common way to control asphaltene agglomeration and precipitation. Until now, it has not been clear why under some conditions the flocculation inhibitors do not inhibit (and may also promote) the asphaltene agglomeration, and why increasing the additive concentration may lead to the diminishing of their efficacy. To clarify this issue, we performed a set of vapor pressure osmometry experiments investigating the asphaltene agglomeration inhibition by commercial and new inhibitor molecules in toluene and o-diclorobenzene. Monte Carlo computer modeling was carried out to interpret some unexpected trends of the averaged molar mass of the Puerto Ceiba asphaltene clusters at different concentrations of inhibitor, assuming that inhibitor efficiency is directly related to their adsorption on the surface of asphaltene. It is shown that the self-assembly of inhibitor molecules, induced by relative lyophilic or lyophobic interactions with a solvent, may be a reason for the inhibitor efficacy declining.