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Abstract Autonomous differential equation compartmental models hold broad utility in epidemiology and public health. However, these models typically cannot account explicitly for myriad factors that affect the trajectory of infectious diseases, with seasonal variations in host behavior and environmental conditions as noteworthy examples. Fortunately, using non-autonomous differential equation compartmental models can mitigate some of these deficiencies, as the inclusion of time-varying parameters can account for temporally varying factors. The inclusion of these temporally varying factors does come at a cost though, as many analysis techniques, such as the use of Poincaré maps and Floquet theory, on non-autonomous differential equation compartmental models are typically only tractable numerically. Here, we illustrate a rare$$n$$ $n$-strain generalized Susceptible-Infectious-Susceptible (SIS) compartmental model, with a general time-varying recovery rate, which features Floquet exponents that are algebraic expressions. We completely characterize the persistence and stability properties of our$$n$$ $n$-strain generalized SIS model for$$n\ge 1$$ $n\ge 1$. We also derive a closed-form solution in terms of elementary functions for the single-strain SIS model, which is capable of incorporating almost any infectious period distribution. Finally, to demonstrate the applicability of our work, we apply it to recent syphilis incidence data from the United States, utilizing Akaike Information Criteria and Forecast Skill Scores to inform on the model’s goodness of fit relative to complexity and the model’s capacity to predict future trends.