Across numerous model systems, aging skeletal muscle demonstrates an impaired regenerative response when exposed to the same stimulus as young muscle. To better understand the impact of aging in a human model, we compared changes to the skeletal muscle transcriptome induced by unaccustomed high-intensity resistance loading (RL) sufficient to cause moderate muscle damage in young (37 yr) vs. older (73 yr) adults. Serum creatine kinase was elevated 46% 24 h after RL in all subjects with no age differences, indicating similar degrees of myofiber membrane wounding by age. Despite this similarity, from genomic microarrays 318 unique transcripts were differentially expressed after RL in old vs. only 87 in young subjects. Follow-up pathways analysis and functional annotation revealed among old subjects upregulation of transcripts related to stress and cellular compromise, inflammation and immune responses, necrosis, and protein degradation and changes in expression (up- and downregulation) of transcripts related to skeletal and muscular development, cell growth and proliferation, protein synthesis, fibrosis and connective tissue function, myoblast-myotube fusion and cell-cell adhesion, and structural integrity. Overall the transcript-level changes indicative of undue inflammatory and stress responses in these older adults were not mirrored in young subjects. Follow-up immunoblotting revealed higher protein expression among old subjects for NF-κB, heat shock protein (HSP)70, and IL-6 signaling [total and phosphorylated signal transducer and activator of transcription (STAT)3 at Tyr705]. Together, these novel findings suggest that young and old adults are equally susceptible to RL-mediated damage, yet the muscles of older adults are much more sensitive to this modest degree of damage - launching a robust transcriptome-level response that may begin to reveal key differences in the regenerative capacity of skeletal muscle with advancing age.