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Objective After the introduction of 13-valent pneumococcal conjugate vaccine (PCV13), a decrease of serotype-3 invasive pneumococcal disease (IPD) has not been homogenously observed around Europe. The aim of the study is to analyze the incidence of serotype-3 IPD in our area (Catalonia, Spain) and describe what microbiological and clinical characteristics distinguish serotype-3 IPD from nonserotype-3 IPD. Methods This study is a prospective observational study performed in three hospitals of Barcelona (Spain), from January 2012 to June 2016. Patients younger than 18 years with a diagnosis of IPD were included. Epidemiological, clinical, and microbiological data were collected. Results A total of 253 cases of IPD were included; of these, 53 were caused by serotype 3. The incidence rate of serotype-3 IPD remained stable over the study years (risk ratio [RR] = 0.64; 95% confidence interval [CI]: 0.3–1.38). In 92.5% (49/53) of the cases of serotype-3 IPD, the diagnosis was pneumonia and 89.8% (44/49) of them reported a complicated pneumonia. Also, 98.1% (52/53) were detected by positive real-time polymerase chain reaction (PCR) in blood or pleural effusion. Seventeen patients were properly vaccinated with PCV13 before the infection. Conclusion After the introduction of PCV13 a global decline of invasive pneumococcal disease has been reported, specially, due to a decrease of serotypes 1 and 19A cases. Serotype-3 Streptococcus pneumoniae IPD remained stable throughout the years of study, being currently the main serotype causing IPD in our area. Serotype 3 causes mostly pneumonia and physicians must be aware of possible complications. Real-time PCR have a significantly higher diagnostic yield for serotype 3 compared with culture. Some vaccination failures were observed.