To explore a mechanism explaining dysregulated CD154 expression in lupus, cell surface CD154 expression was examined, pre- and post-activation, on peripheral blood CD4 T cells from 29 children with lupus and matched controls by flow cytometry. CD154 mRNA levels and transcription rates were studied by real-time RT-PCR and nuclear run-on assays, respectively. NFAT transcriptional activity and NFAT mRNA levels in lupus CD4 T cells were explored by reporter gene analysis and real-time RT-PCR, respectively. We found CD154 surface protein levels were increased 1.44-fold on lupus CD4 T cells compared to controls at one day post-activation ex vivo and this correlated with the presence of nephritis. Increased CD154 protein also correlated with increased CD154 mRNA levels and rates of CD154 transcription, particularly at later time-points post-T cell activation. Reporter gene analyses revealed a trend for increased NFAT, but decreased AP-1 and similar NFkB, activity in lupus CD4 T cell compared to controls. NFAT1 and, in particular, NFAT2 mRNA levels were notably increased in lupus CD4 T cells compared to controls. In summary, following activation, cell surface CD154 is increased on pediatric lupus CD4 T cells compared to controls, and this correlates with the presence of nephritis, increased CD154 transcription rates, and NFAT activity. These results suggest that NFAT/calcineurin inhibitors, such as tacrolimus and cyclosporine, will be beneficial treating lupus nephritis.