Background Homelessness is uncommon but is frequently a characteristic in adults with invasive pneumococcal disease (IPD). In Calgary, homeless persons comprise approximately 0.2% of the population. We evaluated the relationship of homelessness and IPD in Calgary. Methods Demographic, clinical, and microbiologic data were collected by the Calgary Streptococcus pneumoniae Epidemiology Research (CASPER) team through prospective, population-based surveillance of all IPD cases. Here, we report on cases in adults (≥18 years) from 2000 to 2016. Results Of 1729 IPD cases, 321 (18.8%) occurred in homeless persons. Compared with nonhomeless persons, homeless persons were younger, more often male, smokers, alcohol abusers, illegal drug users, and had a primary diagnosis of pneumonia. In multivariable models of outcomes, homeless persons had lower odds of being admitted to the ICU (odds ratio [OR], 0.7; P = .02) and lower odds of death (OR, 0.6; P = .146). IPD caused by serotypes 4, 5, or 8, which have caused outbreaks in Calgary, was more common in homeless persons (54.4% vs 21.0%; P < .001). In addition, regardless of homeless status, persons with IPD caused by serotypes 4, 5, or 8 had lower odds of ICU admission and mortality (OR, 0.7; P = .017; and OR, 0.4; P = .004; respectively). Conclusions Homelessness is overrepresented in IPD cases in Calgary, despite most homeless persons having fewer risk factors than the overall population of persons with IPD. Most cases are caused by serotypes in both the 23-valent polysaccharide vaccine and the 13-valent conjugate vaccine. Thus, enhanced efforts are needed to deliver both vaccines to this vulnerable population.