OBJECTIVES: Presence of underlying medical conditions is believed to increase risk of pneumococcal disease (PD) across all age groups.  However, excess risks of PD attributable to specific conditions are not well known in children or adults, nor are condition-specific attributable economic costs. METHODS: Using healthcare claims information from ~80 million persons annually, plan members during 2007-2010 were stratified into subgroups based on presence of selected “at-risk” chronic conditions (eg, heart, lung, and liver disease, asthma, diabetes) and “high-risk” immunocompromising conditions (eg, malignancies, HIV, chronic renal disease).  At-risk and high-risk conditions, and episodes of invasive pneumococcal disease (IPD) and all-cause pneumonia (PNE), were identified via diagnosis, procedure, and drug codes.  Annual PD rates and PD-attributable healthcare costs (2010US$) among at-risk and high-risk persons versus age-matched healthy counterparts were compared using incidence rate ratios (IRR) and cost ratios; corresponding 95% CIs were estimated using Poisson regression and nonparametric bootstrapping. RESULTS: Annual rates of IPD and PNE were consistently higher among at-risk persons (IRR=3.8 [95% CI 3.5-4.0] and 4.5 [4.5-4.6]) and high-risk persons (IRR=9.3 [8.6-10.0] and 8.2 [8.2-8.3]) versus their healthy counterparts.  Rates were notably high for at-risk persons with asthma (IRR=3.2 [2.8-3.7] and 4.4 [4.4-4.5]), diabetes (IRR=3.8 [3.5-4.2] and 4.6 [4.5-4.6]), or ≥2 at-risk conditions (IRR=8.5 [7.8-9.2] and 10.6 [10.6-10.7]).  Annual PD-attributable healthcare costs totaled $56.1 million per 100,000 at-risk person-years and $118.9 million per 100,000 high-risk person-years, which were 5.2 [5.1-5.2] and 11.0 [10.9-11.0] times higher than corresponding costs for healthy persons. CONCLUSIONS: Rates and costs of PD are substantially higher among persons with certain chronic and immunocompromising conditions versus those without any such conditions.  Rates and costs for persons with asthma and diabetes were especially increased, and rates and costs for individuals with ≥2 at-risk conditions approached those among persons with high-risk conditions.