Background:The most common type of oral cancer is oral squamous cell carcinoma. If it is diagnosed in the early stages; the success of the treatment can be increased. It seems that ELISA-based techniques as a screening tool for society are the most cost-effective methods for early diagnosis. CD44 is a key marker for the detection of SCC stem cells. The aim of this study was to compare the level of soluble CD44 in saliva and serum between patients with oral SCC and healthy controls.Materials and Methods:Saliva and serum were collected from 20 patients with primary OSCC and 20 healthy persons as control group. The samples were evaluated by an ELISA test kit. Data were analyzed by SPSS software version 22, chi-square, ANOVA, T-test and Spearman correlation test.Results:The mean of soluble CD44 level in serum and saliva of the patient and control groups are 531.51±228.95 and 453.3±113.74 (for serum) and 48.53±59.02 and 17.76±39.14 (for saliva) respectively. There was no statistically significant difference in serum and saliva solCD44 level between the patient and control groups (P value = 0.182 and P value = 0.061 respectively). Also, there was no significant correlation between the solCD44 level in each patient and control group in serum (P value = 0.61) and in saliva (P value = 0.445).Conclusions:Determination of solCD44 level in saliva and serum can be a useful method for diagnosis the person’s involvement with cancer cells and the cancer in the early stages. But according to the controversial outcomes of past studies, larger and more accurate studies are needed in groups with more cases of oral cancer.