For reservoir operation, maintaining a quasi-natural flow regime can benefit river ecosystems, but may sacrifice human interests. This study took the Qingshitan Reservoir in the Lijiang River as a case, and developed an optimization model to explore a trade-off solution between social-economic interests and nature flow maintenance on a monthly base. The objective function considered irrigation, cruise navigation and water supply aspects. An index of flow alteration degree was proposed to measure the difference between the regulated discharge and the natural flow. The index was then used as an additional constraint in the model besides the conventional constraints on reservoir safety. During model solving, different criteria were applied to the index, representing various degrees of alteration of the natural flow regime in the river. Through the model, a relationship between social-economic interests and flow alteration degree was established. Finally, a trade-off solution of the reservoir operation was defined that led to a favorable social-economic benefit at an acceptable alteration of the natural flow.