The transcription factor STAT3 has been identified as a mediator of cytokine signaling and implicated in hypertrophy, however the importance of this pathway following resistance exercise in human skeletal muscle has not been investigated. In the present study, the phosphorylation and nuclear localization of STAT3, together with STAT3 regulated genes were measured in the early recovery period following intense resistance exercise. Muscle biopsy samples from healthy subjects (7 males, 23.0 + 0.9 years) were harvested prior to and again at 2 h, 4 h and 24 h into recovery following a single bout of maximal leg extension exercise (3 sets, 12 repetitions). Rapid and transient activation of phosphorylated (tyrosine 705) STAT3 was observed at 2 h post exercise. STAT3 phosphorylation paralleled the transient localization of STAT3 to the nucleus, which also peaked at 2 h post exercise. Downstream transcriptional events regulated by STAT3 activation peaked at 2 h post exercise, including: early responsive genes c-FOS (800-fold), JUNB (38-fold), and c-MYC (140-fold) at 2 h post exercise. A delayed peak in VEGF (4-fold) was measured 4 h post exercise. Finally, genes associated with modulating STAT3 signaling were also increased following exercise including the negative regulator SOCS3 (60-fold). Thus following a single bout of intense resistance exercise, a rapid phosphorylation and nuclear translocation of STAT3 is evident in human skeletal muscle. These data suggest that STAT3 signaling is an important common element and may contribute to the remodelling and adaptation of skeletal muscle following resistance exercise.