Background: Pneumococcal infection causes serious illness in children, especially those with underlying conditions. Although pneumococcal vaccination in the pediatric population is recommended, the immune response to pneumococcal vaccines in this group is usually deficient. The aim of this study was to study the response to pneumococcal vaccines in children with underlying conditions. Methods: A one-year retrospective study on children with underlying conditions attended at the Pediatric Immunology Unit of La Fe University Hospital (Valencia, Spain). Patient demographics, immunosuppressive diseases, pneumococcal vaccination coverage, serum levels of C3, C4, IgA, IgM, IgG, IgG1, IgG2, IgG3, IgG4, blood levels of leukocytes, neutrophils and CD4 and CD8 T lymphocyte were analyzed. Results: A total of 85 children were included in the study. Only 29.41% of them had the complete vaccination schedule, most under 5 years of age (76.00%). Protective levels of pneumococcal antibodies were found only in 48% of the correctly vaccinated patients, whose serum levels of IgG4 and CD4/CD8 ratio were higher than in children with deficient response. Low vaccine response was mostly found among leukemic patients, who exhibited the lowest level of CD4 T lymphocyte. Patients’ age, immunosuppressive therapy, and serum levels of C3, C4, IgG3 and lymphocytes were associated with pneumococcal vaccine response. Conclusion: Most of the patients lacked some dose of pneumococcal vaccine and had an inadequate response. Mathematical models can be useful in clinical practice to detect non responders. Emphasis should be placed on completing a vaccination schedule and, if necessary, revaccination with a booster dose of pneumococcal vaccines.