Cogeneration of heat and power systems based on the organic Rankine cycle (ORC-CHP) has been proven to be an effective way to utilize waste heat at medium and low temperatures. In this work, three ORC-CHP (combined heat and power based on organic Rankine cycle) systems are simulated and compared, including the SS (serial system), the CS (the condensation system), and the SS/CS. The multi-objective genetic algorithm (MOGA) is used to optimize the three systems respectively to achieve higher exergy efficiency and profit ratio of investment (PRI). The optimal thermal-economic performance is obtained. Twelve organic fluids are adopted to evaluate their performance as working fluids. The calculation results show that SS has the highest exergy efficiency, while SS/CS has the best economic performance. Compared with the highest exergy efficiency of SS and the best economic performance of SS/CS, CS will be the optimal solution considering these two objective functions. Under the optimal working conditions, SS has the highest thermal efficiency because it has the highest net power output. The components with the largest proportion of exergy destruction are the heat exchangers, which also has the highest cost.