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One tool in efforts to tackle the ever growing problem of water scarcity is municipal wastewater reclamation to produce drinking water. Microfiltration (MF) is a central technology for potable reuse because it is highly effective in removing pathogenic protozoa, bacteria, and other colloids and for reverse osmosis pretreatment. However, as microfiltered materials accumulate at the membrane surface, its productivity is reduced requiring periodic removal of foulants. A mathematical model of MF is described in the context of hollow fiber filtration that focused on optimizing constant flux operation with backwashing. Design curves were also proposed for determining backwash timing. The model analysis is evaluated against real-world MF fouling for membranes that range in age from a few weeks to three years, observed at the world’s largest water reuse facility operated by the Orange County Water District. The presented model compares well with the full-scale operational data, and model parameters accurately capture variations in fouling kinetics with membrane age, providing clues to changes in optimal regeneration timing and frequency as membrane performance declines over long time scales.