Ab initio calculations in the gas phase and Monte Carlo simulations using the statistical pertubation method in aqueous solution have been carried out to study the tautomeric/conformational equilibria of histamine and (alpha R,beta S)-alpha,beta-dimethylhistamine in both the neutral and protonated forms. The two most stable gas-phase conformers of the neutral histamine molecule are gauche structures stabilized by intramolecular hydrogen bonds. The gauche 1H tautomer is more stable than the gauche 3H structure by 1.7-1.8 kcal/mol at the QCISD/6-31 G*//HF/6-31G* and MP2/ 6-311++G**//HF/6-3 1G* levels after considering frequency dependent corrections for the free energy at 298 K. Trans conformers at these levels are higher in free energy than gauche 1H by 2.3-3.7 kcal/mol. For the monocations protonated at the side chain the second most stable trans 3H form is higher in free energy by 13 kcal/mol than the most stable gauche 3H structure. The relative free energies of the protonated g1H and t1H tautomers are 19-25 kcal/mol. (alpha R,beta S)-alpha,beta-Dimethylation of histamine has an effect mainly on the equilibrium geometries leaving the relative energies close to those obtained for histamine. For the equilibrium mixture of the neutral forms (existing at pH > 9-10 in aqueous solution) 87% trans and 13% gauche conformers were calculated for histamine. The preference for the trans over the gauche conformations may be attributed to the larger number of polar sites opened for hydration in aqueous solution. In the monocationic form prevailing under physiological conditions at pH = 7.4, the gauche 3H tautomer is more stable than the trans 1H structure by about 0.4 kcal/mol leading to 64% gauche and 36% trans conformers. This result is in good agreement with previously reported NMR results in solution at pD = 7.9 that predicted 45% trans form. For both the histamine and the (alpha R,beta S)-alpha,beta-dimethylhistamine solutes the gauche 3H solute is more stable than the trans 3H conformer by about 2 kcal/mol. The theoretical calculations highlight the balance of the internal stabilization and the solvent effect. Solution structure analysis provides rationale for the energy changes in the tautomerization processes and conformational changes upon solvation. The results are discussed in relationship to existing models for histamine receptor activation.