Background Aspirin can inhibit inflammatory reactions and platelet aggregation, but little is known about the effects of the combination of aspirin plus clopidogrel, a new antiplatelet agent, on inflammation. The purpose of this study was to determine whether aspirin plus clopidogrel can further suppress inflammation in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). Methods One hundred and fifteen patients with NSTEACS were randomized into two groups: group A (aspirin alone, n=58) and group B (aspirin plus clopidogrel, n=57). Patients in group A received a loading dose of 300 mg aspirin, then 100 mg per day. The patients in group B received a loading dose of 300 mg aspirin and 300 mg clopidogrel, then 100 mg aspirin and 75 mg clopidogrel per day. Serum high sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-α(TNF-α) were measured in all patients at baseline prior to any drug treatment after admission, and at 7 and 30 days after beginning drug treatment. Thirty healthy volunteers on no medications were enrolled as controls (group C).Results Baseline levels of hs-CRP and TNF-αin group A and group B were significantly higher than those in group C. Seven days after administration, the levels of hs-CRP in both group A and group B decreased significantly [Group A: (6.15 ± 1.39) mg/L vs (9.18 ± 1.62) mg/L, P <0.01; Group B:(4.99 ± 1.62) mg/L vs (10.29 ± 1.47) mg/L, P<0.01]. Similarly, levels of TNF-αin both groups decreased at 7 days compared to baseline [Group A: (90.99 ± 28.91) pg/ml vs (117.20 ± 37.13) pg/ml, P <0.01; Group B: (74.32± 21.83) pg/ml vs (115.27 ± 32.11) pg/ml, P <0.01]. Thirty days after administration, the levels of hs-CRP in both group A and group B decreased further to (3.49 ± 1.53) mg/L, and (2.40 ± 1.17) mg/L respectively (P <0.01 for both comparisons). Levels of TNF-αin groups A and B also decreased significantly between 7 and 30 days, to 63.28 ± 29.01 pg/ml (group A) and (43.95 ± 17.10) pg/ml (group B; P <0.01 for both comparisons). Significantly lower levels of hs-CRP and TNF-αwere observed in group B compared to Group A at thirty days after initiating drug treatment (P <0.05).Conclusions Aspirin plus clopidogrel treatment reduced levels of serum hs-CRP and TNF-α in patients with NSTEACS significantly more than aspirin alone. Because both aspirin and clopidogrel produce important anti-inflammatory effects, these results suggest the possibility that long-term treatment with aspirin plus clopidogrel may produce greater clinical benefits compared to treatment with aspirin alone.