Cycloheximide (CHM) is a known inhibitor of cytoribosomal protein synthesis and has been shown to delay transit of mammalian cells through the cell cycle. Previous studies have shown modification by CHM of the effect of radiation both in vitro and in vivo. To investigate a possible protective effect of the drug on the radiation response of normal tissue, skin reaction and structural damage in the hind limbs were scored in CHM-treated rats exposed to single doses of X irradiation. The drug had no effect on radiation reaction when given immediately before or after X-ray treatment. However, protection against both skin reaction and structural damage was observed when CHM was given at least 6 hr prior to irradiation with maximal protection observed at 12 hr. A similar protective action was seen for the protein synthesis inhibitor emetine. If CHM or other inhibitors of protein synthesis interrupt the normal cell cycle with resultant selective radioprotection of normal tissue, they may enhance the therapeutic effectiveness of radiation. Cycloheximide (CHM) is a glutarimide antibiotic that has been shown to inhibit protein synthesis both in vitro and in vivo. It is known to be specific for cytoribosomal as opposed to mitochondrial protein synthesis, but there are conflicting reports in numerous plant and animal cell systems regarding the primary mode of action. The major inhibitory effect has been variously attributed to the initiation (1-3), elongation (4, 5), and termination (6) phases of messenger RNA translation. CHM has been reported to block transit of cells through the G1 (7) and G2 (8) phases of the cell cycle. It is hypothesized that the drug inhibits synthesis of a labile protein regulating growth (7, 9). Transformed tumor cell lines with defective growth control have been shown to be less sensitive to CHM-induced cycle arrest (10). The therapeutic effectiveness of ionizing radiation should be enhanced by agents which selectively increase the radioresistance of normal tissue without modifying the radiation response of tumor cells. The cell-cycle-active agents hydroxyurea (11 ) and cytosine arabinoside (12) have been shown to induce radioresistance in mouse intestinal cells, presumably at least partially on the basis of synchronization of cells into relatively radioresistant phases of the cell cycle. If CHM selectively modifies