Tumor necrosis factor-alpha (TNF-alpha) can inhibit tumor progression. It can be regulated by its soluble receptors (sTNF-Rs). We examined the expression of TNF-alpha and sTNF-Rs and the TNF-alpha/sTNF-R ratios in betel-quid-chewing patients with oral squamous cell carcinoma (OSCC) to see if these parameters are associated with disease progression according to the treatment stage. Peripheral blood mononuclear cells from 116 OSCC patients at different treatment stages and 19 betel-quid chewers with normal mucosa were assayed with ELISA. Levels of sTNF-RII in the OSCC patients were significantly higher than normal controls, with the recurrence group having the highest levels. After controlling for age and use of alcohol and tobacco, the TNF-alpha/sTNF-RII ratio showed significant differences comparing OSCC patients at each treatment stage with normal controls. Our results suggest that sTNF-RII and TNF-alpha/sTNF-RII ratio may be informative for the diagnosis and prognosis of OSCC.