Aim: To evaluate the efficacy and safety of amtolmetin guacyl in the management of osteoarthritis (OA) of knee and associated dyspepsia in routine clinic setting. Methods:In an observational study conducted in the OA outpatients between February 2015 and December 2015, patients with knee joint (KJ) pain ≥ 40 mm on visual analogue scale (VAS) and dyspepsia were enrolled. Amtolmetin guacyl 600 mg tablets twice daily was administered for up to 28 days. Patients were evaluated at baseline, Day 14 ± 3, and at Day 28 ± 3 for severity of pain in "target" knee (VAS), Western Ontario and Mc master Universities Arthritis (WOMAC) pain and stiffness, and severity of dyspepsia assessment (SODA). Results:Of the 219 OA patients, approximately 72.5% patients reported decrease in pain in the target KJ by ≥ 40% at the end of the study. Mean pain reduced from 65 mm at baseline to 27 mm at the end of the study. A significant decrease in WOMAC pain score, morning stiffness, and functional limitations were also observed (P<0.001). A significant decrease in severity of dyspepsia assessment (SODA) score and increase in satisfaction was observed. Amtolmetin tolerability was comparatively better than previously used NSAIDS. Conclusion:Amtolmetin guacyl is effective and safe in OA patients with associated dyspepsia and has comparatively better tolerability than other NSAIDS. This trial is registered with http://clinicaltrials.gov, number NCT02865161.