AbstractInterleukin‐38 (IL‐38) has recently been considered as a cytokine with anti‐inflammatory properties in viral respiratory infections, particularly coronavirus disease 19 (COVID‐19), but the evidence has not been well elucidated. Therefore, a case‐control study was conducted to determine IL‐38 serum levels in 148 patients with COVID‐19 (45 moderate, 55 severe, and 48 critical) and 113 controls. Results demonstrated that IL‐38 levels did not show significant differences between patients and controls (68.7 [interquartile range: 62.7–75.6] vs. 67.7 [58.0–82.6] pg/ml; probability = 0.457). Similarly, patients stratified by disease severity, age group, gender, or chronic disease showed no significant differences between IL‐38 levels in each stratum. Whereas, overweight/obese patients had a significantly lower median of IL‐38 compared to normal‐weight patients. Further, IL‐38 showed significantly higher levels in the age group ≥50 years of patients with critical illness than in the age group <50 years. Female patients with severe disease also showed significantly elevated levels of IL‐38 compared to male patients. In conclusion, the study indicated that serum IL‐38 levels were not affected by COVID‐19 infection, but the distribution of patients according to disease severity, age, gender, and body mass index may better reveal the role of IL‐38 in disease pathogenesis.