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Abstract Physiological closed-loop control algorithms play an important role in the development of autonomous medical care systems, a promising area of research that has the potential to deliver healthcare therapies meeting each patient's specific needs. Computational approaches can support the evaluation of physiological closed-loop control algorithms considering various sources of patient variability that they may be presented with. In this article, we present a generative approach to testing the performance of physiological closed-loop control algorithms. This approach exploits a generative physiological model (which consists of stochastic and dynamic components that represent diverse physiological behaviors across a patient population) to generate a select group of virtual subjects. By testing a physiological closed-loop control algorithm against this select group, the approach estimates the distribution of relevant performance metrics in the represented population. We illustrate the promise of this approach by applying it to a practical case study on testing a closed-loop fluid resuscitation control algorithm designed for hemodynamic management. In this context, we show that the proposed approach can test the algorithm against virtual subjects equipped with a wide range of plausible physiological characteristics and behavior and that the test results can be used to estimate the distribution of relevant performance metrics in the represented population. In sum, the generative testing approach may offer a practical, efficient solution for conducting preclinical tests on physiological closed-loop control algorithms.