Objectives: By the analysis of plasma mRNA levels, we tested the hypothesis that, in human atheroma, CTSS activation coexists with activation of CD40. Design and methods: mRNAs were isolated from plasma of patients with coronary atherosclerosis and quantified by real-time RT-PCR. Results: CTSS mRNA levels correlated with CD40 mRNA levels, independently of observed traditional risk factors for atherosclerosis and pharmacological treatment. Conclusions: Our results suggest that CTSS mediated atherogenesis may be associated with a CD40 mediated inflammatory and immune response. Further invasive atheroma analysis is reasonable.