Objective: To investigate the clinical relevance of serum interleukin-2 receptor α (IL-2Rα) in patients with systemic lupus erythematosus (SLE). Methods: One hundred and seven SLE patients and 39 healthy controls with comparable age and gender were recruited at Peking University People’s Hospital from January 2019 to December 2020. Complete clinical data in 107 SLE patients at baseline and follow-up were collected. SLE disease activity index 2000 (SLEDAI-2K) was used to assess the disease activity of the SLE patients. The serum level of IL-2Rα in the SLE patients and healthy controls was measured using enzyme-linked immunosorbent assay (ELISA). The association between serum IL-2Rα and clinical and laboratory parameters was investigated. Mann-Whitney U test or t test, Chi-square test and Spearman correlation were used for statistical analysis. Results: The serum IL-2Rα levels were significantly higher in the SLE patients [830.82 (104.2-8 940.48) ng/L], compared with those in the healthy controls [505.1 (78.65-1 711.52) ng/L] (P<0.001). Association analysis showed that the increased serum IL-2Rα was positively associated with SLEDAI-2K scores and anti-nucleosome antibody (r=0.357, P<0.001; r=0.25, P=0.027, respectively). Thirty-six of 107 (33.6%) SLE patients had lupus nephritis. Serum IL-2Rα levels were significantly higher in the patients accompanied with lupus nephritis [1 102.14 (126.52-8 940.48) ng/L] than in the patients without lupus nephritis [743.89 (104.19-4 872.06) ng/L] (P=0.032). The patients in the high IL-2Rα group had more lupus nephritis compared with those in the low IL-2Rα group (40.8% vs. 19.4%, P=0.031). Meanwhile, SLEDAI-2K scores were found significantly higher in the high IL-2Rα group than in the low IL-2Rα group [10 (3-21) vs. 7 (3-16), P=0.001]. With the improvement of disease activity in the SLE patients after conventional treatments, serum levels of IL-2Rα [1 119.1 (372.25-2 608.86) ng/L] in the week 12 decreased significantly compared with the baseline [1 556.73 (373.08-8 940.48) ng/L] (P=0.042). Conclusion: Serum IL-2Rα may be used as a biomarker of disease activity in patients with SLE. There is certain correlation between serum IL-2Rα and renal involvement in SLE.