Pro-inflammatory and anti-inflammatory cytokines are indicated to play a prominent role in mediating the immunopathogenesis of coronavirus disease 19 (COVID-19). Interleukin (IL-37) is one of the anti-inflammatory cytokines that has been proposed to be involved in disease progression but the data are not overwhelming. Therefore, a case-control study was performed to analyze IL-37 levels in serum of 100 patients with severe COVID-19 and 100 blood donors (control group). Median age was significantly higher in COVID-19 cases than in controls. Stratification by gender, body mass index and ABO and Rh blood group systems showed no significant differences between patients and controls. Chronic diseases (cardiovascular and diabetes) were observed in 57.0% of patients. Serum levels of IL-37 and vitamin D were significantly decreased in patients compared to controls. The low level of IL-37 was more pronounced in males, overweight/obese cases, blood group B or AB cases, Rh-positive cases, and cases with no chronic disease. Low producers of IL-37 were more likely to develop COVID-19 (odds ratio = 2.66; 95% confidence interval = 1.51–4.70; corrected probability = 0.015). Receiver operating characteristic curve analysis demonstrated that a low serum level of IL-37 was a good predictor of COVID-19. Spearman's rank correlation analysis showed that IL-37 and vitamin D were significantly correlated. In conclusion, IL-37 was down-regulated in serum of patients with severe COVID-19 compared to controls. This down-regulation may be associated with an increased risk of disease. Gender, body mass index, blood groups and chronic disease status may also affect IL-37 levels.