Introduction: Streptococcus pneumoniae is the most frequent cause of overwhelming post-splenectomy infections. Pneumococcal vaccination is generally recommended for splenectomized individuals. However, most of our knowledge comes from a few observational studies or small randomized clinical trials. We conducted this systematic review to assess the evidence of efficacy, antibody response, and the best timing for pneumococcal vaccination in splenectomized individuals. Areas covered: The systematic review was conducted according to the PRISMA guidelines. We screened 489 articles, included 21 articles, and assessed the risk of bias using Cochrane RoB 2 and ROBINS-I. We summarized the findings narratively due to the heterogeneity of the studies. Expert opinion: Splenectomized individuals seem to have adequate antibody responses to pneumococcal vaccines. No differences in antibody responses were observed compared to healthy controls, except in one study. The studies were heterogeneous, and the majority had moderate to high degree of bias. There is a lack of clinical evidence for efficacy and best timing of pneumococcal vaccination in splenectomized individuals. Randomized clinical trials addressing these issues are needed.