BACKGROUND: Previous small studies have indicated that commonly prescribed drugs may be associated with microscopic colitis (MC). With an increasing incidence of MC, it is important to explore the association between exposure to proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs, statins, and selective serotonin reuptake inhibitors and MC in a larger setting. METHODS: Case-control study based on nationwide Danish registries. The study included all patients with MC diagnosis during the period 2005 to 2011. One hundred sex- and age-matched controls per case were randomly selected among the Danish population. Prescriptions were recorded in a Prescription Register in the year before the first recorded MC diagnosis. Effect measure is the adjusted odds ratio (OR) of collagenous colitis (CC) and lymphocytic colitis (LC) according to prescriptions of PPIs, nonsteroidal anti-inflammatory drugs, statins, and selective serotonin reuptake inhibitors. Within the control group, we identified a subgroup with MC-free colonic biopsies. RESULTS: We identified 3474 patients with CC and 2277 with LC and found a positive association between redemption of prescriptions for PPIs and both CC (OR = 7.04; 95% confidence interval, 6.55-7.56) and LC (OR = 3.37; 95% confidence interval, 3.08-3.69). Among patients with MC-free colon biopsies in the control group, the association between PPIs and CC was strongly positive (OR = 3.47; 95% confidence interval, 3.08-3.89). Adding this parameter to the model attenuated all of the associations, but they remained positive for PPIs versus CC and selective serotonin reuptake inhibitors versus LC. CONCLUSIONS: We found positive associations between exposure to all 4 medication classes and MC. Variations in endoscopic frequency by drug category indicate a potential impact of bias.