OBJECTIVES: To investigate the association between the level of adherence to GPAs and the risk of serious NSAID-related UGI complications in patients using non-selective NSAIDs (nsNSAIDS). METHODS: A population based nested case-control study was conducted within a cohort of new NSAID users with at least one risk factor for a NSAID-related UGI complication identified in the Dutch Integrated Primary Care Information database between 1996-2005. Adherence to GPAs was calculated as the proportion of NSAID treatment days covered (PDC) by a GPA prescription. Multivariate conditional logistic regression analysis was used to calculate adjusted odds ratios (OR) with 95% confidence intervals (95%CI). RESULTS: Considering the most recent episode of continuous nsNSAID use prior to the index date, 14.9% of the nsNSAID users received GPAs. Of these, 71.0% had a PDC ratio >80% (full adherence), 22.0% PDC ratios between 20-80% (partial adherence) and 7.0% being non-adherent (PDC<20%). The risk of a serious NSAID-related UGI complication increased from 2.5 (95%CI:1.0-6.7) in partially adherent persons to 4.0 (95%CI:1.2-13.0) in those with a PDC<20%. Considering the PDC level as a continuous measure, the risk of a serious NSAID-related UGI complication increased with 16% (95%CI:2-32%) with every 10% decrease in adherence. Excluding H2RA users that were not adequately dosed for the prevention of NSAID-related UGI complications, the risk was increased 2.7-fold in patients that were partially adherent and 4.5-fold in patients that were non-adherent. CONCLUSION: There is a strong relationship between the level of adherence to gastroprotective medication and the risk of serious UGI complications in high-risk nsNSAID users. This underlines the need for adequate patient instruction regarding adherence to GPAs and/or the further development of fixed combination strategies.