Introduction: In clinical practice, it has been observed that patients with severe infections show changes to their hematocrit (HCT) and serum albumin (ALB) levels. This study aimed to evaluate whether the difference of HCT and ALB (HCT-ALB) levels can be used as an additional biomarker for fast diagnosis of severe infections. Material and methods: This was a retrospective case-control study which included adult patients with severe infections, patients with non-infective conditions and healthy individuals. A total of 7,117 individuals were recruited in Yunnan Province, China, from January 2012 to January 2018, and were divided into three groups: 1,033 patients with severe infections (group 1); 1,081 patients with non-infective conditions (group 2); and 5,003 healthy individuals from the general population (group 3). The potential diagnostic threshold of HCT-ALB for severe infectious patients was determined by the receiver operating characteristic (ROC) curve analysis. Group 3 was used as the reference to draw the ROC curves of the HCT-ALB value in group 1 or group 2. Results: HCT-ALB values in each group were significantly different. We found that the area under the ROC curve (AUC) of group 1 reached 0.87 (95% CI: 0.86 0.89), whereas the AUC of group 2 was 0.60 (95% CI: 0.58 0.62). To reach a higher specificity of 99.0% (95% CI: 98.8 99.3%, and with sensitivity of 37.5%, 95% CI: 34.5 40.5%), a HCT-ALB value of 10.25 was recommended as the standard for diagnosis of severe infection. Conclusions: The HCT-ALB value was increased in patients with infectious disease. The measurement of the HCT-ALB value (> 10.25) might be useful in the fast diagnosis of infectious disease.