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When the estimated parameter values are close to the true values, the probability density function of output with the estimated will be close to the probability density function with the true parameter values. Based on this idea, a new method is proposed to estimate unknown parameters using output probability density function. To cope with shortcomings of estimation algorithms of output probability density function, anther performance function is also proposed based on the histogram of model output. In order to illustrate the effectiveness and robustness of this method, HIV/AIDS model is taken as an example and the simulation results are encouraging.