Abstract Background Despite being one of the most commonly used and readily available drugs worldwide, we still do not understand why non-steroidal anti-inflammatory drugs (NSAIDs) increase cardiovascular risk. A proteomics approach may provide mechanistic insight into how COX-2 protects the cardiovascular system. Purpose To use SWATH proteomics to identify cardiovascular biomarkers in NSAID users who go onto have a cardiovascular event. Methods A case control study was designed using the Standard Care Versus Celecoxib Outcome Trial (SCOT) biobank (1). Serum samples from 228 NSAID users with osteoarthritis were analysed. From these, an exploratory analysis of 15 individuals who had a cardiovascular event within 6 months were compared to 213 individuals who did not. SWATH proteomics was used to identify biomarkers and findings were validated by immunoassay. Results Seventy-eight proteins were detected at significantly different levels in serum from participants who did or did not have an event within 6 months of enrolment. Of these the greatest increase in the event group was in levels of the renal dysfunction marker, cystatin C (Log Fold difference 1.4, p<0.001). Validation using a renal biomarker immunoassay panel confirmed a higher level of cystatin C (Z-score 0.6 vs −0.04, p: 0.02) as well as a lower level of uromodulin (Z-score −0.5 vs 0.03, p: 0.036) in the event group. In agreement, mass spectrometry analysis identified a higher level of the cardio-renal biomarker asymmetric dimethylarginine (ADMA) in the event group (Z-score 0.4 vs −0.03, p: 0.07) (Figure 1). Conclusion Renal biomarkers are associated with early cardiovascular events amongst NSAID users in the SCOT cohort. Thus, changes in renal function should be investigated as a mechanistic or predictive factor in this population at elevated cardiovascular risk. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation