BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed to control pain, inflammation, and fever in upper respiratory tract infections (URTIs). AIM: To explore the relative effectiveness and gastrointestinal (GI)-related safety of individual NSAIDs to control symptoms of URTIs. METHOD: Using an Italian primary care data source, we identified patients aged ≥ 15 years who were newly prescribed NSAIDs for URTIs between 2013 and 2022. Switching to another NSAID for the same indication within the 30-day follow-up was a proxy for drug effectiveness. The study outcome for GI safety analysis was upper gastrointestinal bleeding (UGIB). RESULTS: In a cohort of 57,971 patients, the most prevalent subgroups were those treated with ketoprofen (39.5%) and dexibuprofen/ibuprofen (22.4%). Ketoprofen showed the lowest rate of switching to another NSAID [Hazard Ratio (HR) 0.40 (95% CI 0.20-0.83)] against acetylsalicylic acid/coxibs/diclofenac. Dexibuprofen/ibuprofen showed similar results [HR 0.50 (95% CI 0.22-1.10)], with no significant association. Ketoprofen and dexibuprofen/ibuprofen were prescribed as lysine and arginine salts in 85 and 6% of URTIs sufferers, respectively. Across NSAIDs, we did not find any significant difference in the risk of UGIB. CONCLUSION: Our findings indicated that various NSAIDs may exhibit differing levels of effectiveness in treating URTIs, particularly those formulated for quick onset of action. No NSAIDs-UGIBs association was found. Further prospective, larger studies are needed to confirm these findings.