OBJECTIVES: The risk of gastrointestinal ulcers is enhanced by non-steroidal anti-inflammatory drugs (NSAID). Proton pump inhibitors (PPI) are used for gastroprotection, but their effectiveness has been documented only in few studies (Hooper et al. BMJ 2004; 329:948-57). We therefore investigated in the gastroprotective effects of PPI on diclofenac-induced ulcer risk. METHODS: A nested case control study was performed based on claims data from a large German sickness fund. A cohort was constructed consisting of all beneficiaries enrolled in the health plan continuously from 2000 until 2004. Cases had an inpatient treatment due to peptic ulcer starting at or after January 1st 2003 with the case onset being the index date. All other beneficiaries were randomly allocated to an index date, and ten controls per case were drawn. For the 90 days before the index date it was checked, if diclofenac and/or PPI were dispensed. The influence of diclofenac alone as well as with concomitant PPI prescription on ulcer risk was analysed using logistic regression models. RESULTS: We identified 979 cases and 10,319 controls in the cohort of 752,613 beneficiaries. The stratified analysis according to the prescription of diclofenac alone or in combination with PPI showed that diclofenac prescriptions within the 90 days before the index day increased the risk for hospitalization due to peptic ulcer significantly (odds ratio (OR) 3.21; 95%CI 2.59-3.96; p<0.001). The risk was reduced (OR 1.26; 95%CI 0.68-2.30; p=0.46), if PPI were prescribed concomitantly with diclofenac. The significance of the PPI effect was demonstrated by inserting an interaction term in a regression model without stratification, where a risk reduction of 63% (OR 0.37; 95%CI 0.18-0.74; p=0.005) was found. CONCLUSION: The concomitant prescription of PPI and diclofenac decreases the hospitalization risk due to peptic ulcer thus supporting the use of PPI as gastroprotective agents.