National infectious disease incidence rates are often estimated by standardizing locally derived rates using national-level age and race distributions. Data on other factors potentially associated with incidence are often not available in the form of patient-level covariates. Including characteristics of patients' area of residence may improve the accuracy of national estimates. The authors used data from the Centers for Disease Control and Prevention's Active Bacterial Core Surveillance program (2004-2005), adjusted for census-based variables, to estimate the national incidence of invasive pneumococcal disease (IPD). The authors tested Poisson and negative binomial models in a cross-validation procedure to select variables best predicting the incidence of IPD in each county. Including census-level information on race and educational attainment improved the fit of both Poisson and negative binomial models beyond that achieved by adjusting for other census variables or by adjusting for an individual's race and age alone. The Poisson model with census-based predictors led to a national estimate of IPD of 16.0 cases per 100,000 persons as compared with 13.5 per 100,000 persons using an individual's age and race alone. Accuracy of, and confidence intervals for, these estimates can only be determined by obtaining data from other randomly selected US counties. However, incorporating census-derived characteristics should be considered when estimating national incidence of IPD and other diseases.