There are no approved treatments for liver fibrosis. To aid development of antifibrotic therapies, noninvasive biomarkers that can identify patients with progressive fibrosis and that permit monitoring of the response to antifibrotic therapy are much needed. Samples from a phase II antifibrotic trial of the glitazone farglitazar in patients with advanced hepatitis C, with matched follow-up liver biopsies, and from a phase III study of balaglitazone in patients with late-stage Type 2 diabetes (BALLET study) were analyzed for serological Pro-C3 levels in conjunction with other disease parameters. In the farglitazar study, a predefined cutoff value for Pro-C3 as a selection criterion led to the identification of subjects who 1) progressed by histological scores and 2) responded to therapy, as documented by attenuated fibrosis in liver biopsies. In the BALLET trial, subjects with the highest tertile of Pro-C3 levels responded to balaglitazone with reductions in levels of alanine aminotransferase and Pro-C3, as well as improved insulin sensitivity and lipid profile. Elevated Pro-C3 levels are indicative of active fibrogenesis and structural progression of fibrosis, and it can potentially identify patients most likely to benefit from antimetabolic and antifibrotic treatments. Serum Pro-C3 may facilitate patient selection and could help to speed up antifibrotic drug development and validation.