Activation of DNA synthesis in prothoracic gland cells of the silkworm, Bombyx mori, during the middle stages of the last larval instar appears to be nutrition dependent, with starvation on day 3 of the last larval instar inhibiting its dramatic increase. The possible cellular mechanism causing the inhibition of DNA synthesis owing to starvation was further examined by determining changes in the growth-promoting activity of the hemolymph and the responsiveness of gland cells to starvation. The results showed that on starvation, the activity of the growth-promoting factor in the hemolymph did not greatly decrease until 2 days after starvation had begun. However, the dramatic increase in the responsiveness of gland cells (the ability to synthesize DNA when exposed to the hemolymph growth factor), which normally occurs on day 4 of the last instar, was not observed when starvation was begun on day 3. A dramatic increase in gland cell size was observed in control larvae during later stages of the last larval instar. However, with starvation beginning on day 3, gland cell size was maintained at lower levels compared with those of control larvae, indicating that the inhibition of DNA synthesis is indeed related to the inhibition of cell size. From these results, it was assumed that alterations in growth factor receptors and downstream signaling may be related to the inhibition of DNA synthesis by starvation and that the deficiency in growth-promoting factor signaling may guarantee that the growth of endoreplicative tissues in these larvae ceases.