Mechanisms mediating post-exercise cold-induced increases in PGC-1α gene expression in human skeletal muscle are yet to be fully elucidated, but may involve local cooling effects on AMPK and p38 MAPK related signalling and/or increased systemic β-adrenergic stimulation. We aimed to therefore examine whether post-exercise cold-water immersion enhancement of PGC-1α mRNA is mediated through local or systemic mechanisms. Ten subjects completed acute cycling (8x5 min at ~80% peak power output) followed by seated-rest (CON) or single-leg cold-water immersion (CWI; 10 min, 8°C). Muscle biopsies were obtained pre-, post- and 3 h post-exercise from a single limb in the CON condition but from both limbs in CWI (thereby providing tissue from a CWI and non-immersed limb, NOT). Muscle temperature decreased up to 2 h post-exercise following CWI (-5°C) in the immersed limb, with lesser changes observed in CON and NOT (-3°C; P<0.05). No differences between limbs were observed in p38MAPK phosphorylation at any time point (P<0.05), whilst a significant interaction effect was present for AMPK phosphorylation (P=0.031). Exercise (CON) increased gene expression of PGC-1α 3 h post-exercise (~5-fold; P<0.001). CWI augmented PGC-1α expression above CON in both the immersed (CWI; ~9-fold; P=0.003) and NOT limbs (~12-fold; P=0.001). Plasma Normetanephrine concentration was higher in CWI vs. CON immediately post-immersion (860 vs. 665 pmol/L; P=0.034). We report for the first time that local cooling of the immersed limb evokes transcriptional control of PGC1-α in the non-immersed limb, suggesting increased systemic β-adrenergic activation of AMPK mediates, in part, post-exercise cold-induction of PGC-1α mRNA.