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Reliable estimates of population size are important for developing and monitoring health programs in at-risk populations. Laska, Meisner, and Siegel (Biometrics 1988;44:461–72) developed an unbiased estimator for the size of a population at a single venue based on a single sample. Because many populations of interest are not contained within a single venue, this article generalizes the Laska, Meisner, and Siegel estimator to incorporate two- and three-stage sampling designs and enable estimation of total population size over multiple venues. Use of the estimator with two- and three-stage sampling designs is illustrated with examples that estimate the size of a population of individuals who socialize over a 4-week period at public venues where transmission of human immunodeficiency virus and other sexually transmitted infections is likely to occur.