Abstract Background: Lupus is one of the most common autoimmune diseases. IFN-α as an important factor in the pathogenesis of lupus has been introduced. Also, CD26 with its enzymatic activity has many roles in the regulation of immune responses. In the current study, we investigated the level of CD26 and IFN-α in the serum of SLE patients. Materials and methods: In this case-control study, 46 SLE patients and 44 sex and age-matched controls enrolled. Patients were grouped into subgroups of active patients (n=24) and inactive (n=22), or nephritis patients (n=17) and non-nephritis patients (n=29). Serum level of sCD26 and IFN-α were measured by ELISA and the Mann-Whitney test was used for statistical analysis. Results: Difference between patients and controls in serum levels of CD26 (438.96±137 vs. 579.66±409 ng/mL) and IFN-α (73.93±31.7 vs. 62.36±7.5 pg/mL) was not significant. Additionally, the concentration of sCD26 between active and inactive patients was not significant. A significant elevated level of sCD26 was observed in patients with nephritis vs. non-nephritis patients (771.4±553 vs. 467.26±243 ng/mL, p<0.05). Conclusion: In regards to the roles of sCD26, significant elevation in sCD26 level in lupus nephritis patients could be considered as a sign of anti-inflammatory responses. Therefore, measurement of serum sCD26 as a biomarker can define new criterion for measuring anti-inflammatory responses.