Patients undergoing autologous hematopoietic stem cell transplantation (autoHCT) are at increased risk for infection with Streptococcus pneumoniae and have impaired antibody responses to pneumococcal polysaccharide vaccines. We performed this study to examine the ability of autoHCT patients to respond to a heptavalent pneumococcal conjugate vaccine (PCV7) given after transplantation and to determine whether there was a potential benefit of immunizing these patients before stem cell collection. Sixty-one patients scheduled for autoHCT were randomized to receive either PCV7 or no vaccine before stem cell collection. After stem cell reinfusion, all study patients were immunized with PCV7 at 3, 6, and 12 months. Pneumococcal immunoglobulin G antibody concentrations were measured at the time of each immunization and 1 month after the 12-month dose. Serotype-specific pneumococcal antibody concentrations were significantly higher in patients immunized with PCV7 before stem cell collection compared with patients not immunized before their stem cells were collected for 6 of 7 serotypes at 3 months, 6 of 7 serotypes at 6 months, 4 of 7 serotypes at 12 months, and 3 of 7 serotypes at 13 months. After the 3-dose series of PCV7 after autoHCT, >60% of study patients had protective concentrations of antibody to all 7 vaccine serotypes regardless of immunization before stem cell collection. Pneumococcal conjugate vaccine is immunogenic in autoHCT patients and may be an effective strategy to prevent invasive disease after transplantation.