We have investigated the potential use of differential scanning calorimetry (DSC) to characterize conformational changes in proteins with emphasis on a conformational change in the myosin head which may be related to the power-stroke providing force production in muscle contraction. Simulations indicate that two-state conformational transitions with enthalpy changes greater than approximately 30 kcal/mol should be observable by DSC. We present here differential scanning calorimetric studies of a predenaturation structural change in heavy meromyosin. The high concentration of protein required for these experiments leads to potential contributions from intermolecular interactions. The technical difficulties associated with studying conformational transitions by DSC are discussed.