Abstract Aims To examine whether non-aspirin non-steroidal anti-inflammatory drug (NSAID) use is associated with increased cardiovascular risks in patients with non-obstructive coronary artery disease (CAD). Methods and results Using Danish medical registries, we conducted a population-based cohort study in Western Denmark during 2008–17. We identified all patients undergoing first-time coronary computed tomography angiography (CCTA) due to suspected CAD (n = 35 399), with results showing no (n = 28 581) or non-obstructive CAD (n = 6818). Multivariate Cox regression was used to compute hazard ratios of major adverse cardiac events (MACEs), including incident myocardial infarction, coronary intervention, and death. The rate of MACE increased by 33% for any NSAID use compared with non-use [hazard ratio 1.33, 95% confidence interval (CI) 1.06–1.68] in patients with no CAD and by 48% (1.48, 95% CI 1.06–2.07) in patients with non-obstructive CAD. Rate difference of MACE, per 100 person-years, was 0.38 (95% CI 0.08–0.67) in patients with no CAD (number needed to harm: 267) and 1.08 (95% CI 0.06–2.11) in patients with non-obstructive CAD (number needed to harm: 92). Current use of older cyclooxygenase-2 inhibitors was associated with the highest hazard ratio in patients with non-obstructive CAD, both when ascertained as pre-CCTA use (2.9-fold increase) and when ascertained from time-varying use (1.8-fold increase). Conclusion NSAID use in patients with CCTA-confirmed no and non-obstructive CAD was associated with an increased cardiovascular risk compared with non-use. The absolute risk differences and numbers needed to harm were considered clinically relevant, particularly in patients with non-obstructive CAD.