It is difficult to distinguish the early phase of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) from other ordinary types of drug-induced skin reactions (ODSRs). Levels of several serum soluble factors, including soluble Fas ligand (sFasL), have been reported to be increased in patients with SJS/TEN; however, the marker to predict the onset of SJS/TEN before the development of skin detachment or mucosal lesions has not been identified. We sought to determine whether sFasL might be a useful marker in the early stages of SJS/TEN. Sera of 19 patients with SJS and 16 patients with TEN at 1 or multiple time points were obtained from Japanese multiple hospitals. The disease onset (day 1) was defined when erosion/ulceration of the mucocutaneous or ocular lesion first developed. For the investigation of soluble factors, including sFasL, TNF-alpha, IFN-gamma, IL-6, and sCD40 ligand, we used ELISAs and Cytometric Bead Arrays. Before disease onset (day -4 to approximately -2), 7 samples were available, and we detected the highest concentrations of sFasL in 5 (71.4%) of 7 patients. Increased sFasL levels decreased rapidly within 5 days of disease onset. In all 32 patients with ODSRs and 33 healthy control subjects, no increase of sFasL levels was detected. Other soluble factor concentrations did not show significant difference with those seen in patients with SJS/TEN before disease onset and ODSRs. The sFasL levels of sera in patients with SJS/TEN are significantly increased before development of skin detachment, mucosal lesions, or both.