Hydrogen peroxide (H2O2) acts as a signaling messenger by oxidatively modifying distinct cysteinyl thiols in distinct target proteins. However, it remains unclear how redox-regulated proteins, which often have low intrinsic reactivity towards H2O2 (kapp ∼1-10 M(-1) s(-1)), can be specifically and efficiently oxidized by H2O2. Moreover, cellular thiol peroxidases, which are highly abundant and efficient H2O2 scavengers, should effectively eliminate virtually all of the H2O2 produced in the cell. Here, we show that the thiol peroxidase peroxiredoxin-2 (Prx2), one of the most H2O2-reactive proteins in the cell (kapp ∼10(7)-10(8) M(-1) s(-1)), acts as a H2O2 signal receptor and transmitter in transcription factor redox regulation. Prx2 forms a redox relay with the transcription factor STAT3 in which oxidative equivalents flow from Prx2 to STAT3. The redox relay generates disulfide-linked STAT3 oligomers with attenuated transcriptional activity. Cytokine-induced STAT3 signaling is accompanied by Prx2 and STAT3 oxidation and is modulated by Prx2 expression levels.