Joining polysaccharide antigens to protein increases immunogenicity in infants. In older adults, using conjugation to protein carriers to improve the immune response to pneumococcal polysaccharide vaccine has thus far proved disappointing. Low immunity to the carrier protein in the elderly may explain the failure of conjugated vaccines to elicit a T-cell-dependent response. We immunized 49 older adults (ages 60-78) and 50 younger adults (ages 18-45) with either 23-valent pneumococcal polysaccharide (PS) vaccine or 5-valent CRM197-conjugated pneumococcal oligosaccharide. Sera obtained before and after vaccination were analyzed for antibody to pneumococcal serotypes 14 and 6B and diphtheria toxin by ELISA. Baseline diphtheria toxin antibody level was lower in older adults than in younger adults (0.31 and 0.88 IU/ml, respectively; p < 0.0001). Adults with higher diphtheria antibody level had a higher antibody level to PS type 6B after vaccination than those with lower diphtheria antibody level (9.9 vs. 3.5 microg/ml, respectively; p = 0.01). Antibody level to PS type 14 was higher, but differed by baseline anti-diphtheria antibody level only when the older group was evaluated alone. Low levels of antibody to diphtheria protein may explain some of the lower responses to conjugate pneumococcal vaccine in older adults.