Manganese superoxide dismutase (MnSOD) is a nuclear encoded and mitochondrial matrix-localized redox enzyme that is known to regulate the cellular redox environment. Cellular redox environment changes during transitions between quiescent and proliferative cycles. HumanMnSODhas two poly(A) sites resulting in two transcripts: 1.5 and 4.2 kb. The present study investigates if the 3′-untranslated region (UTR) ofMnSODregulates its expression during transitions between quiescent and proliferating cycles, and in response to radiation. A preferential increase in the levels of the 1.5-kbMnSODtranscript was observed in quiescent cells, whereas the abundance of the longer transcript showed a direct correlation with the percentage of S-phase cells. The log-transformed expression ratio of the longer to the shorter transcript was also higher in proliferating normal and cancer cells. Deletion and reporter assays showed a significant decrease in reporter activity in constructs carrying multiple AU-rich sequence that are present in the 3′-UTR of the longerMnSODtranscript. Overexpression of theMnSOD3′-UTR representing the longer transcript enhanced endogenousMnSODmRNA levels, which was associated with an increase in MnSOD protein levels and a decrease in the percentage of S-phase cells. Irradiation increases the mRNA levels of the 1.5-kbMnSODtranscript, which was consistent with a significant increase in the reporter activity of the construct carrying the 3′-UTR of the shorter transcript. We conclude that the 3′-UTR ofMnSODregulatesMnSODexpression in response to different growth states and radiation.