Apoptosis in tumor and normal tissues was examined in rats treated with whole-body hyperthermia (WBH; 41.5 degrees C for 2 h). WBH alone produced 0.5 day of tumor growth delay (TGD) in a fibrosarcoma and 5.8 days of TGD in the Ward colon carcinoma. This difference in WBH-induced TGD indicates that the fibrosarcoma is relatively resistant to WBH, whereas the Ward colon carcinoma is relatively heat sensitive. A quantitative histological assay for apoptosis demonstrated that the extent of apoptosis in the fibrosarcoma reached a maximum level of 19% 4 h after WBH and returned to the control level by 24 h. In contrast, WBH induced apoptosis with a peak value of 43% at 8 h in the Ward colon carcinoma, and the apoptotic level remained elevated above the control level until 48 h after WBH. Within normal tissues, the spleen and the lymph nodes showed WBH-induced apoptosis; however, the highest level of WBH-induced apoptosis as well as the most prolonged increase in apoptotic levels occurred in the thymus. The WBH-induced apoptosis in the thymus remained elevated above the control level until 48 h after WBH. Within the entire gastrointestinal tract, the small intestine was the most sensitive to WBH. Apoptotic cells were observed in the small bowel mucosa following WBH exposure. We also noted a minor WBH-induced increase in the apoptotic level in the bone marrow. Except for the case of the thymus, increased apoptotic levels in the normal tissues declined after peak levels at 4 h, and apoptosis above control levels was not seen beyond 12 h following WBH. Thus, within the normal tissues, WBH-induced apoptosis declined to basal levels within 12-48 h. These data indicate that both the extent and the kinetics of WBH-induced apoptosis differ between the two tumors and, meaningfully, between tumor and normal tissues. The extent and duration of apoptosis seem to correlate with tumor response to WBH.