Background <p>Diabetes mellitus (DM) is a disease with a high prevalence worldwide. It is, indeed, a risk factor for invasive pneumococcal disease (IPD), which is a serious infection caused by <i>Streptococcus pneumoniae</i> (SP), also known as pneumococcus. To analyze invasive pneumococcal disease (IPD) in Spanish patients hospitalized with diabetes mellitus (DM), related with influenza, COVID-19, and RSV disease, and other comorbidities.</p> Methods <p>Discharge reports from the Spanish Minimum Basic Data Set were used to retrospectively analyze hospital data with a diagnosis of DM from 1997 to 2022. Patients with type 1 diabetes and type 2 diabetes were included with no age restrictions. Primary outcome was first hospitalization for IPD in patients with DM and secondary was cause-specific mortality. Differences in continuous variables were analyzed using Student’s t-test, while categorical variables were evaluated using chi square test. Risk factors for IPD in patients with DM were studied as odds ratio (OR). Logistic regression analysis was performed to identify the factors associated with infection risk after DM and effect estimates.</p> Results <p>A total of 12,923,632 patients with DM were identified from the Spanish database. 442,859 (3.43%) patients with type 1 DM and 12,480,773 (96.57%) patients with type 2 DM were determined. Infection with <i>Streptococcus pneumoniae</i> was 0.50 and 0.66%, respectively. The study demonstrated a higher risk of hospitalization for IPD in patients with type 1 DM compared to type 2 DM. The risk of IPD-related hospitalization associated with DM was greater in those with comorbidities (type 1 DM) and low with respect to Influenza, COVID-19, and RSV disease (<i>p</i> ≤ 0.001).</p> Conclusions <p>Epidemiological analysis showed that DM and other comorbidities are relevant for IPD, and have a meaningful impact in the Spanish health system.</p>