Pentoxifylline (PENTO), a derivative of methylxanthine, has been reported to improve fluidity of red blood cells (RBC), and thus improve the flux of RBC through narrow capillaries. Additionally, PENTO increases 2,3-DPG levels in RBC, thereby increasing the O2 release from RBC. Nicotinamide (NA) has been known to increase tumor blood flow, reducing the hypoxic cell fractions in the tumors. The purpose of this study was to examine the effects of PENTO alone or in combination with NA (PENTO + NA) on the oxygenation and radio-response of FSaII murine fibrosarcomas of mice. We observed a significantly enhanced, radiation-induced growth delay of the FSaII tumors by the treatment of either single or multiple injections of PENTO. The combination of PENTO and NA further delayed the growth of tumors. The TCD50 of control tumors was about 56.6 Gy, whereas that of PENTO + NA treated tumors was about 31.9 Gy. Thus, TCD50 was modified by a factor of 1.8. PENTO + NA exerted no effect on the acute skin damage of C3H mice after local irradiation and the gastrointestinal death after whole body irradiation. However, PENTO + NA slightly increased the bone marrow death as demonstrated by the decrease in LD50(30) from 5.5 Gy to 5.2 Gy. The average pO2 in the saline-treated control group of FSaII tumors was 8 mmHg and it significantly increased to 19 mmHg in the PENTO + NA treated group (p less than 0.001). We concluded that the PENTO + NA treatment increased the radio-response of tumors by improving tumor oxygenation.