Background: There are no approved treatments for liver fibrosis. To aid development of anti-fibrotic therapies, non-invasive biomarkers that can identify patients with progressive fibrosis and that permit monitoring of the response to anti-fibrotic therapy are much needed. Methods: Samples from a phase II anti-fibrotic 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 late stage type 2 diabetics (BALLET study), were analysed for serological Pro-C3 levels in conjunction with other disease parameters. Results: In the farglitazar study, a pre-defined cut-off value for Pro-C3 as selection criterion led to identification of those subjects who a) progressed by histological scores and b) 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 ALT and Pro-C3, as well as improved insulin sensitivity and lipid profile. Conclusions: Elevated Pro-C3 levels are indicative of active fibrogenesis and structural progression of fibrosis and can potentially identify patients most likely to benefit from anti-metabolic and potential anti-fibrotic treatments. Serum Pro-C3 may facilitate patient selection and could help to speed up anti-fibrotic drug development and validation.