Carbon monoxide is a biologically active molecule produced in the body by the stress-inducible enzyme heme oxygenase. We have previously shown that carbon monoxide suppresses fibrosis in a murine bleomycin model. To investigate the mechanisms by which carbon monoxide opposes fibrogenesis, we performed gene expression profiling of fibroblasts treated with transforming growth factor-1 and carbon monoxide. The most highly differentially expressed categories of genes included those related to muscular system development and the small proline rich family of proteins. We confirmed in vitro and in an in vivo bleomycin model of lung fibrosis that carbon monoxide suppresses -smooth muscle actin expression and enhances small proline rich protein-1a expression. We further show that these effects of carbon monoxide depend upon signaling via the extracellular-signal regulated kinase (ERK) pathway. Our results demonstrate novel transcriptional targets for carbon monoxide and further elucidate the mechanism by which carbon monoxide suppresses fibrosis.