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Introduction Mitigations intended to reduce bone mineral loss in-flight also influence the level of renal stone risk to astronauts. Extending a recent study completed by our group [1], we investigate the likely influence of combined fluid intake and Ca excretion mitigation strategies. Methods A computational biochemistry model representing CaOx crystal precipitation, growth, and agglomeration [2] is combined with a probabilistic analysis to predict the in-flight CaOx renal stone incidence risk ratio (IRR) relative to pre-flight values using 1517 astronaut 24-hour urine chemistries. The output of this simulation is used to assess the combined impact of controlling fluid intake and Ca excretion on maintaining IRR < 1.2 for > 95% of the population, a threshold determined from initial analysis of the model output compared to referent populations [1]. Results and Conclusions Figure 1 illustrates the simulated in-flight astronaut population (n=40000) with CaOx IRR > 1.2. The red lines indicate the known clinical risk boundary of each factor, and the white box is considered the area of high combined clinical risk. The simulation and identified risk threshold conform well to the expected clinical risk boundaries. The results, assuming insensible water losses equal or exceed 0.7 L/day, imply mitigations achieve risks similar to pre-flight levels when either Ca < 150 mg/day or fluid volume intake > 3.2 L/day individually, or combined Ca < 200 and fluid volume intake > 2.5 L/day. We continue to investigate similar compounded effects and look to apprise engineering trades by informing relative risk changes during mission design. References [1] D. A. Goodenow-Messman, S. A. Gokoglu, M. Kassemi, and J. Myers, Jerry G., “Characterization of Astronaut CaOx Renal Stone Incidence Rates to Quantify In-flight and Post-flight Relative Risk,” npj Microgravity, in review, 2021. [2] M. Kassemi and D. Thompson, “Prediction of renal crystalline size distributions in space using a PBE analytic model. 1. Effect of microgravity-induced biochemical alterations,” Am. J. Physiol. Physiol., vol. 311, no. 3, pp. F520–F530, Sep. 2016, doi: 10.1152/ajprenal.00401.2015.