The influence of the solvents dichloromethane and chloroform on the conformational distribution of a tetramethoxycalixarene 2b (R = t-Bu) has been investigated by 1H NMR and molecular modeling with the charmm force field. This calixarene derivative can exist in the cone, partial cone, 1,2-alternate, and 1,3-alternate conformations. The cone/partial cone equilibrium showed the largest solvent effect during measurements in CD2Cl2 and CDCl3. The conformational distribution of 2b was calculated in a vacuum with the Boltzmann equation based on the sum of the minimized potential energies and the vibrational and rotational free energies. The influence of the solvent was investigated by molecular dynamics simulations. These simulations show that the cavity of the cone of 2b contains a solvent molecule in dichloromethane, but not in chloroform. Although the inclusion of a chloroform molecule is enthalpically favorable, it is not stable because of the unfavorable entropy of complex formation. In both chloroform and dichloromethane, one conformer (0001∼aaab) is the most stable Paco; in this conformation the methoxy moiety connected to the inverted aromatic ring is pointing into the cavity of 2b. The increased stability of this conformer is due to the possibility to form CH··O hydrogen bonds.