The ocean thermal energy conversion (OTEC) system is a promising solution to provide stable electricity supply. Although the available temperature difference in OTEC systems is small, an ammonia/water mixture as working fluid is expected to decrease irreversible losses in the heat exchangers and to improve system performance. However, in actual heat exchangers, an adequate temperature crossing does not occur in the condenser but in the evaporator. Therefore, clarification of this characteristic is important. To date, the logarithmic temperature difference (LMTD) method is used in performance evaluations of OTEC heat exchangers. This method is of limited use if physical properties of fluids vary. A generalized mean temperature difference (GMTD) method is introduced to perform this evaluation. As changes in fluid property values can be considered in the GMTD method, method dependencies on heat exchanger characteristics, effectiveness, and system characteristics can be studied. In particular, GMTD and LMTD using a pure substance were found to be almost equal. Mean temperature differences using mixtures as working fluid were higher in the evaporator, but lower in the condenser, from the GMTD method than from the LMTD method. For higher ammonia concentrations in ammonia/water mixtures, the mean temperature differences from both methods are different.