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Background: The international surveillance of antimicrobial resistance (AMR) reports S. pneumoniae as one of leading causes of death associated with AMR. Against invasive disease, several vaccinations are available and a reduction in AMR in S. pneumoniae has been observed. Here, we evaluated the impact of anti-pneumococcal vaccination policy and the SARS-CoV2 outbreak on AMR in S. pneumoniae causing invasive disease. Methods: We collected all strains of S. pneumoniae causing invasive disease from 2008 in the Piedmont region (Italy). Each strain was typed in order to identify the serogroup and data about AMR were collected. The population under surveillance was classified as infants, children, adults, and the old population. Results: We collected n = 2076 S. pneumoniae strains, with 21.9% and 40.3% being resistant to penicillin G and erythromycin, respectively. We reported an increased risk of infection with penicillin-resistant S. pneumoniae among all populations and evaluated whether the infection was caused by a serotype included in the vaccine formulation. A similar increase was observed after the SARS-CoV2 outbreak. Conclusions: In the Piedmont region, subsequently to the introduction of anti-pneumococcal vaccination, a significant increase in the risk of penicillin G-resistant invasive pneumococcal disease among infants and old population was reported. No significant impact was found for the SARS-CoV2 outbreak.