Suitable diet for cancer survivors remains an unresolved challenge. Increased glucose utilization is a hallmark of various cancers. Therefore, alternative carbohydrate supplying normal tissue but retarding cancer growth is needed. This study investigated the effect of sugar alcohols on the proliferation of oral cancer cells compared to nontransformed cells and explored the mechanism. Six oral squamous cell carcinoma (CAL-27, FaDu, SCC4, SCC9, SCC15, and SCC25) and one nontransformed oral keratinocyte (OKF6/TERT2) lines were cultured in media containing 1 mg/ml glucose and 5.8 mg/ml xylitol or sorbitol, yielding equal energy input to control group (4.5 mg/ml glucose). Partial substitution of glucose with sugar alcohols especially xylitol significantly suppressed proliferation of oral cancer but not nontransformed cells. Despite the addition of isocaloric quantities of the sugars, cancer cells exposed to low glucose plus xylitol had retarded ATP generation and decreased activity of phosphofructokinase (PFK), the rate-limiting enzyme in glycolysis. Furthermore, D-xylulose, its key metabolic intermediate, enhanced the anticancer effect of xylitol. These findings suggested a selective anticancer activity of xylitol and the potential mechanism involving inhibition of glucose utilization. Partial substitution of glucose with xylitol may be a proper nutrient for oral cancer survivors, deserving further investigation in animal and clinical settings.