Models of entire managed systems, known as operating models or management strategy evaluation (MSE) models, have been developed in recent years to more fully account for uncertainty in multiple steps of fishery management. Here we describe an operating model of sea lamprey management in the Great Lakes and use the model to compare alternative management strategies for sea lamprey control in Lake Michigan. Control of sea lampreys is mainly achieved through the application of chemical lampricides that target stream-dwelling larvae before they become parasites. The operating model simulated uncertainty due to process variation in larval population dynamics, the accuracy of population assessments used to direct selection of areas to be chemically treated, and the effectiveness of these treatments. We used the operating model to compare the performance of stream selection strategies that either rely on assessments to direct chemical treatments or eliminate the assessment process altogether by relying on prior but uncertain knowledge of stream-level sea lamprey growth rates to specify a fixed schedule for chemical treatments. The fixed schedule strategy led to a modest improvement in expected suppression of parasitic sea lamprey abundance over the assessment-based strategy so long as assessment cost savings were allocated to chemical treatment when assessment was not used to select streams for treatment. We also evaluated the sensitivity of the assessment-based strategy to differing but plausible levels of assessment uncertainty. A moderate reduction in assessment uncertainty led to a large increase in suppression of parasitic sea lamprey abundance for the assessment-based selection strategy, emphasizing the importance of both accurately measuring and reducing assessment uncertainty.