Degradation of Myc protein is mediated by E3 ubiquitin ligases, including SCF(Fbw7) and SCF(Skp2), but much remains unknown about the mechanism of S-phase kinase-associated protein (Skp2)-mediated Myc degradation. In the present study, we show that upregulated Myc protein, which triggers the G1-S phase progression in response to growth-stimulatory signals, induces reactive oxygen species modulator 1 (Romo1) expression. Romo1 subsequently triggers Skp2-mediated ubiquitylation and degradation of Myc by a mechanism not previously reported in normal lung fibroblasts. We also show that reactive oxygen species (ROS) derived from steady-state Romo1 expression are necessary for cell cycle entry of quiescent cells. From this study, we suggest that the generation of ROS mediated by pre-existing Romo1 protein is required for Myc induction. Meanwhile, Romo1 expression induced by Myc during G1 phase stimulates Skp2-mediated Myc degradation in a negative-feedback mechanism.