Objective.To perform a prospective evaluation of soluble CD40 ligand (sCD40L) levels according to the activity of systemic lupus erythematosus (SLE).Methods.Two serum samples were taken from 53 patients with SLE: at flare and at remission. Clinical and biological measures (sCD40L levels were measured by a commercial ELISA) were evaluated in both situations.Results.Patients with SLE had significantly lower median levels of sCD40L during flare than during remission [3365 (6157) vs 7125 (4122) pg/ml; p < 0.001]. The multivariate analysis to explain those patients with lower values of sCD40L during flare than during remission included 3 variables: 2 related to flare (prednisone dose received ≤ 15 mg/day and platelet counts > 192,000 × 10⁶/l) and one related to lower changes in SLE Disease Activity Index (SLEDAI) score. We regrouped patients with the 2 characteristics related to flare as Group 4, and the others were Group 123. All patients with low SLEDAI scores at flare had statistically significant lower sCD40L levels during flare than during remission. When flare SLEDAI scores were higher than the 50th percentile, patients of Group 123 showed the same behavior and even more diminished levels of sCD40L during flare than patients of Group 123 with low SLEDAI scores (p = 0.023); and patients of Group 4 showed no differences in the values of sCD40L between flare and remission (p = 0.241).Conclusion.sCD40L plays a biologically active role, with decreased levels at flare at low SLEDAI scores. At high SLEDAI scores there are mechanisms that involve platelets and that are inhibited by high doses of prednisone that lead to increased serum values of sCD40L at flare.