Background: Higher consumption of antimicrobials plays an important role in driving the higher prevalence of antimicrobial resistance in Southern compared to Northern Europe. Poor controls on corruption (CoC), high uncertainty avoidance (UA) and performance vs. cooperation orientation (POCO) of societies have been found to explain much of this higher consumption in Southern European countries. We hypothesized that these predictors were in turn influenced by the Protestant Reformation in the 16th century onwards. Methods: We used structural equation modelling (SEM) to assess the relationships between country-level proportions being Protestant, CoC, UA, POCO and four markers of antimicrobial consumption in the community (all antibacterials, cephalosporin, macrolides and fluoroquinolones). Results: The proportion of a country that was Protestant was negatively correlated with the consumption of all antibacterials. SEM revealed that UA predicted all antibacterial consumption (direct effect coef. 0.15, 95% Confidence Interval [CI] 0.04-0.26). The proportion Protestant exerted an indirect effect on consumption (coef. -0.13, 95% CI -0.21- -0.05). This effect was mediated predominantly via its effect on UA (direct effect coef. 0.15, 95% CI 0.04-0.26). The model explained 37% of the variation in consumption. Similar results were obtained for each of the other three classes of antimicrobials investigated. Conclusions: Our results are compatible with the theory that contemporary differences in antimicrobial consumption in Europe stem in part from cultural differences that emerged in the Reformation. These findings may explain the differential efficacy of similar antibiotic stewardship campaigns in Northern and Southern European populations.