Despite the availability of vaccines against Streptococcus pneumoniae, the global incidence and economic cost of pneumococcal disease (PD) among adults is still high. This retrospective cohort analysis estimated the cost of emergency department (ED) visits/hospitalizations associated with non-invasive pneumonia and invasive pneumococcal disease among individuals ≥15 years of age in the Liguria region of Italy during 2012–2018. Data from the Liguria Region Administrative Health Databases and the Ligurian Chronic Condition Data Warehouse were used, including hospital admission date, length of stay, discharge date, outpatient visits, and laboratory/imaging procedures. A ≥30-day gap between two events defined a new episode, and patients with ≥1 ED or inpatient claim for PD were identified. The total mean annual number of hospitalizations for PD was 13,450, costing ~€49 million per year. Pneumonia accounted for the majority of hospitalization costs. The median annual cost of hospitalization for all-cause pneumonia was €38,416,440 (per-capita cost: €26.78) and was €30,353,928 (per-capita cost: €20.88) for pneumococcal and unspecified pneumonia. The total number and associated costs of ED visits/hospitalizations generally increased over the study period. PD still incurs high economic costs in adults in the Liguria region of Italy.