OBJECTIVES: Patients with gastrointestinal (GI) risk factors who take non-steroidal anti-inflammatory drugs (NSAIDs) should also take gastroprotective agents (GPAs). No studies have evaluated adherence and reasons for non-adherence to GPA and NSAID therapies. METHODS: This was a prospective, multicenter, observational, longitudinal study. Patients attending rheumatology/orthopedic clinics who were co-prescribed NSAID plus GPA for at least 15 days and had risk factors for GI complications were followed up by telephone call. Optimal adherence was defined as taking the drug for ≥80% of prescribed days. Multivariate logistic regression analysis was used to determine factors associated with non-adherence. RESULTS: Of 1,232 patients interviewed, 192 were excluded because of inaccurate data. Of the remaining 1,040 patients, 74% were prescribed low-dose NSAIDs and 99.8% were prescribed a standard or high-dose GPA. In all, 70% of NSAIDs and 63.1% of GPA prescriptions were short term (<30 days). The majority of patients who were prescribed either an NSAID (92.5%) or GPA (85.9%) started therapy. Optimal adherence to GPA or NSAIDs was reported by 79.7% (95% confidence interval (CI): 76.9−82.2%) and 84.1% (95% CI: 81.7−86.3%) of patients, respectively. More adverse events occurred among patients who reported non-optimal adherence than among patients with optimal adherence to GPA (22.1 vs. 1.9%, P<0.0001). As reasons for non-adherence, patients most frequently cited infrequent/low-intensity rheumatic pain (NSAIDs) or forgetfulness (GPAs). Adverse events and short-term treatment were independent factors associated with poor adherence for both NSAIDs and GPAs. History of uncomplicated peptic ulcer and frequent dosing were additional factors associated with non-adherence to NSAIDs. CONCLUSIONS: Most frequent reasons for non-adherence are infrequent/low-intensity rheumatic pain (NSAIDs) or forgetfulness (GPAs). Short-term treatment and adverse events were associated with poor adherence for both therapies.