In this study, we analyzed the clinical and molecular epidemiology of invasive serotype 5 (Ser5) pneumococcal isolates in four teaching hospitals in the Barcelona, Spain, area (from 1997 to 2011). Among 5,093 invasive pneumococcal isolates collected, 134 (2.6%) Ser5 isolates were detected. Although the overall incidence of Ser5-related invasive pneumococcal disease (IPD) was low (0.25 cases/100,000 inhabitants), three incidence peaks were detected: 0.63/100,000 in 1999, 1.15/100,000 in 2005, and 0.37/100,000 in 2009. The rates of Ser5 IPD were higher among young adults (18 to 64 years old) and older adults (>64 years old) in the first two peaks, whereas they were higher among children in 2009. The majority (88.8%) of the patients presented with pneumonia. Comorbid conditions were present in young adults (47.6%) and older adults (78.7%), the most common comorbid conditions being chronic obstructive pulmonary disease (20.6% and 38.3%, respectively) and cardiovascular diseases (11.1% and 38.3%, respectively). The mortality rates were higher among older adults (8.5%). All Ser5 pneumococci tested were fully susceptible to penicillin, cefotaxime, erythromycin, and ciprofloxacin. The resistance rates were 48.5% for co-trimoxazole, 6.7% for chloramphenicol, and 6% for tetracycline. Two major related sequence types (STs), ST1223 (n = 65) and ST289 (n = 61), were detected. The Colombia(5)-ST289 clone was responsible for all the cases in the Ser5 outbreak in 1999, whereas the ST1223 clone accounted for 73.8% and 61.5% of the isolates in 2005 and 2009, respectively. Ser5 pneumococci are a frequent cause of IPD outbreaks in the community and involve children and adults with or without comorbidities. The implementation of the new pneumococcal conjugated vaccines (PCV10 and PCV13) might prevent such outbreaks.