This study investigates the effects of working fluids on the performance of an organic Rankine cycle (ORC) used in an Ocean Thermal Energy Conversion (OTEC) power plant. Working fluids of R1123, R161, R32 and their mixtures are employed. Parameters of pinch points, temperatures of deep cold and surface warm seawater, and efficiencies of pumps and expander are taken into consideration. The objective functions are either net power output or economic performance parameter, respectively. A numerical approach, gradient descent, is employed to solve the optimum mass fractions of mixture working fluids in the OTEC system. The results show that for pure working fluids, the net power output of the OTEC system using R1123 is 620.76 kW and is the highest, followed by R32 and R161, respectively. The economic performance parameter of the OTEC system using R32 is 6.28 m2/kW and is the best, followed by R1123 and R161, respectively. For net power output and economic performance, the two-component mixtures all outperform their pure working fluids of which they are composed. As for three-component mixture, the maximum Wnet and the minimum β and λ of R1123/R161/R32 mixture working fluid are obtained as 945.77 kW, 5.41 m2/kW, and 0.223 $/kW-h with the corresponding mass fractions of 0.72/0.18/0.1, 0.25/0.16/0.59, and 0.12/0.46/0.42, respectively. In addition, the three-component mixture, R1123/R161/ R32, performs best among all the working fluids, which is about 52.36% better than R1123 in net power output and is about 32% better than R717 in economic performance.