Objective This population-based cohort study assesses the impact of switching from a 7-valent pneumococcal conjugate vaccine (PCV) to a 10-valent PCV on outpatient antibiotic use in Dutch infants, and whether geographical vaccination coverage modifies this association. Setting and participants We extracted 2006–2013 anonymised antibiotic purchase data of 255 154 Dutch infants aged below 2 years from Achmea Health, a health insurance fund covering 28% of the national population. Design and main outcome measure Changes in monthly antibiotic use from 2006–2011 (PCV7) to 2011–2013 (PCV10) were estimated using time-series analysis accounting for seasonality and autocorrelation. Interaction terms for vaccination coverage (categorised into seven groups) and period were added to the model to test whether this association was vaccination coverage-dependent. Results 275 337 antibiotic courses were used by 119 078 infants (461 352 person-years). PCV10 introduction was associated with a modest 1.6% overall reduction in antibiotic use (purchase rate ratio: 0.98, 95% CI: 0.98 to 0.99). Our model showed a significant difference in time trend in antibiotic use after PCV10 introduction (p = 0.0084) with an increase in prescriptions in the PCV7 period (slope: 0.0023/month, 95% CI: −0.0001 to 0.0047) versus a decline in the PCV10 period (slope: −0.0089/month, 95% CI: −0.0150 to −0.0029). There was no evidence that PCV vaccination coverage affected this association, but since the largest rate ratios were observed in municipalities with the lowest vaccine coverage and had very wide accompanying CIs, our study might have insufficient power to detect such an association. Conclusions Switching from PCV7 to PCV10 was associated with a modest decline in outpatient antibiotic use in Dutch infants.