Vertical ionization potentials (IPs) of nucleobases embedded in a fully solvated DNA fragment (12-mer B-DNA fragment 22 sodium counterions + 5760 water molecules equilibrated to 298 K) have been calculated using a combined quantum mechanical molecular mechanics (QM/MM) approach. Calculations of the vertical IP of the anion Cl- arc reported that support the accuracy of the application of a QM/MM method to this problem. It is shown that the pi nucleotide HOMO origin for the emitted electron is localized on the base by the hydration structure surrounding the DNA in a way similar to that recently observed for pyrimidine nucleotides in aqueous solutions (Slavicek, P.; et al. J. Am. Chem. Soc. 2009, 131, 6460). In a first step, a high level of theory. CCSD(T)/aug-cc-pVDZ, was used to calculate the vertical IP of each of the four single bases isolated in the QM region while the remaining DNA fragment, counterions, and water solvent molecules were included in the MM region. The calculated vertical IPs show a large positive shift of 3.2-3.3 eV compared to the corresponding gas-phase values. This shift is similar for all four DNA bases. The origin of the large increase in vertical IPs of nucleobases is found to be the long-range electrostatic interactions with the solvation structure outside the DNA helix. Thermal fluctuations in the fluid can result in IP changes of roughly I eV on a picosecond time scale. IPs of pi-stacked and H-bonded clusters of DNA bases were also calculated using the same QM/MM model but with a lower level of theory, B3LYP/6-31G(d=0.2). An IP shift of 4.02 eV relative to the gas phase is found for a four-base-pair B-DNA duplex configuration. The primary goal of this work was to estimate the influence of long-range solvation interactions on the ionization properties of DNA bases rather than provide highly precise IP evaluations. The QM/MM model presented in this work provides an attractive method to treat the difficult problem of incorporating a detailed long-range structural model of physiological conditions into investigations of the electronic processes in DNA.