Analytical second derivatives for combined QM/MM calculations have been formulated and implemented in the CHARMM program interfaced with the ab initio quantum mechanical GAMESS and CADPAC programs. This makes possible evaluation of vibrational frequencies and infrared intensities in large systems that cannot be treated effectively by QM or MM alone; examples are polarizable molecules in solution and substrates or transition states in enzymes. Test calculations on a number of systems, including formamide in water, butanol, a model transition state structure for triosephosphate isomerase and the active site model of myoglobin, show that the MM description of the environment can capture much of its polarization effects on the QM region. Thus the implementation of analytical second derivatives within the QM/MM framework has considerable potential for the study of large systems.