Several cytokines have been implicated individually in the pathogenesis of systemic lupus erythematosus (SLE) and some, including interleukin (IL)-10, IL-12 and IL-1ra are raised during flares of disease activity. Few studies have been directed at examining the interactions between these cytokines and how their combined profile relates to disease activity. We have examined serum levels of IL-10, IL-12 and IL-1ra in a cohort of SLE patients obtained from the Queen Elizabeth Hospital, Birmingham in cross-sectional and, in a smaller group, longitudinal analyses. In the cross-sectional study, there were significant correlations between levels of the three cytokines. There were also significant correlations between levels of each cytokine and measures of disease activity. IL-10 levels correlated with ESR, anti-dsDNA antibody titres and C3D, IL-12 levels with anti-dsDNA antibody titres and IL-1ra levels with ESR, anti-dsDNA antibody titres and C3D. IL-1ra levels also correlated with CRP. Circulating IL-10 and IL-1ra levels were higher in patients with SLE than in normal controls, although in this study group they did not reach significance. Circulating IL-12 levels were, however, significantly higher in SLE compared to controls. This was true both in patients with active disease and those sampled during a quiescent phase. These data add to the evidence that cytokines such as IL-10, IL-12 and IL-1ra are important in SLE pathogenesis. In a retrospective study of serial serum samples from seven patients, we found two patients whose cytokine profile was very different from the rest of the group. In most patients normalized IL-10, IL-12 and IL-1ra levels mirrored BILAG scores closely, but in these two patients, IL-10, IL-12 and IL-1ra levels did not fluctuate with disease activity. It is possible that there is a subgroup of SLE patients whose cytokine profile could be an important indicator of their pathology. In order to confirm this and determine the frequency of such patients this study needs to be repeated with a much larger subject group. The coexistence of patient groups with different patterns of cytokine activity might explain conflicting reports of associations of levels of particular cytokines with SLE. As the observed differences could reflect different aetiologies of SLE, this information could reveal valuable endophenotypes for genetic and functional studies of SLE and might, ultimately, inform therapeutic management.