Community-acquired pneumonia (CAP) is a common cause of sepsis. Active full-length caspase-12 (CASP12L), confined to the people of African descent, has been associated with increased susceptibility to and mortality from severe sepsis. The objective of this study was to determine whether CASP12L was a marker for susceptibility and/or severity of CAP. We examined three CAP cohorts and two control populations: 241 adult Memphis African American CAP patients, 443 pediatric African American CAP patients, 90 adult South African CAP patients, 120 Memphis healthy adult African American controls and 405 adult Chicago African American controls. Clinical outcomes including mortality, acute respiratory distress syndrome (ARDS), septic shock or severe sepsis, need for mechanical ventilation, and S. pneumoniae bacteremia. Neither in the three individual CAP cohorts nor in the combined CAP cohorts, was mortality in CASP12L carriers significantly different from that in non-CASP12L carriers. No statistically significant association between genotype and any measures of CAP severity was found in any cohort. We conclude that the functional CASP12L allele is not a marker for susceptibility and/or severity of CAP.