Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme which suppresses T lymphocyte activity. IDO activity can be determined by relating kynurenine, the main metabolite of tryptophan, to tryptophan (kyn/trp). We have demonstrated recently that systemic lupus erythematosus (SLE) is activated during the sunny season as measured by the European Consensus Lupus Activity Measurement Index (ECLAM) activity score. Our aim here was to establish whether IDO-dependent mechanisms are involved in the activation process of SLE. Kyn/trp was measured by reverse-phase high-performance liquid chromatography (HPLC) in 33 (30 female, three male) SLE patients in winter, spring and summer and in 309 healthy control subjects. At the same time-points the SLE patients were examined by a rheumatologist and a dermatologist and the activity of SLE assessed by the ECLAM score. IDO activity was higher in SLE patients than in healthy subjects. There was no seasonal variation in IDO activity in SLE patients and it did not correlate with the ECLAM activity score in winter. However, there was a significant correlation between IDO activity and the ECLAM score both in spring and in summer. High IDO activity in winter predicted subsequent activation of SLE in spring and summer. Our results indicate that IDO-dependent immunosuppressive mechanisms are activated in SLE patients. Exposure to sunlight or another factor causing seasonal variation in SLE activity leads to insufficiency of this suppression in a subgroup of patients, causing activation of SLE. High IDO activity in winter predicts activation of SLE in the sunny season.