Fascioliasis is caused by the genetically and phenotypically very close Fasciola hepatica and F. gigantica. The latter, always considered secondary in human infection, appears nowadays increasingly involved in human endemic areas of Africa and Asia. Unfortunately, little is known about the pathogenicity of this liver fluke species, mainly due to difficulties assessing the moment of a patient's infection in the anamnesis and in the differential diagnosis with F. hepatica. This is the first experimental study comparing F. hepatica and F. gigantica in a long-term study of up to 24 weeks with genotypically and phenotypically standardised fluke strains in the same animal model host, the Guirra sheep breed susceptible to both species. Serum biochemical parameters of liver damage (aspartate aminotransferase AST, alanine aminotransferase ALT, γ-glutamyl transferase GGT, total bilirubin, alkaline phosphatase AP), serum electrolytes (calcium, chloride, phosphore), protein metabolism (creatinine, blood urea nitrogen), plasma proteins (albumin, total proteins), carbohydrate metabolism (glucose, amylase), hepatic lipid metabolism (total cholesterol, triglycerides) and inflammation (C-reactive protein), were analysed on a biweekly basis as morbidity indicators. Serum anti-Fasciola IgG, coproantigen and egg shedding were simultaneously followed up. DNA sequencing of rDNA ITS-2 and ITS-1 and mtDNA cox1 and nad1, as well as the morphometric study by CIAS, showed the two fasciolid strains used to fit respective standard species characteristics. Results demonstrated that F. gigantica is more pathogenic than F. hepatica, mostly due to its bigger size. Fasciola gigantica shows a delayed development of 1-2 weeks regarding both biliary phase and beginning of egg laying, with the respective consequences on the biochemical marker profile modifications in both the acute and chronic periods. A review on the physiopathogenicity by F. gigantica compared to that by F. hepatica is made. A biochemical marker baseline for human infection by F. gigantica is proposed to help physicians and health officers in F. gigantica human endemic areas.Fascioliasis is caused by the genetically and phenotypically very close Fasciola hepatica and F. gigantica. The latter, always considered secondary in human infection, appears nowadays increasingly involved in human endemic areas of Africa and Asia. Unfortunately, little is known about the pathogenicity of this liver fluke species, mainly due to difficulties assessing the moment of a patient's infection in the anamnesis and in the differential diagnosis with F. hepatica. This is the first experimental study comparing F. hepatica and F. gigantica in a long-term study of up to 24 weeks with genotypically and phenotypically standardised fluke strains in the same animal model host, the Guirra sheep breed susceptible to both species. Serum biochemical parameters of liver damage (aspartate aminotransferase AST, alanine aminotransferase ALT, γ-glutamyl transferase GGT, total bilirubin, alkaline phosphatase AP), serum electrolytes (calcium, chloride, phosphore), protein metabolism (creatinine, blood urea nitrogen), plasma proteins (albumin, total proteins), carbohydrate metabolism (glucose, amylase), hepatic lipid metabolism (total cholesterol, triglycerides) and inflammation (C-reactive protein), were analysed on a biweekly basis as morbidity indicators. Serum anti-Fasciola IgG, coproantigen and egg shedding were simultaneously followed up. DNA sequencing of rDNA ITS-2 and ITS-1 and mtDNA cox1 and nad1, as well as the morphometric study by CIAS, showed the two fasciolid strains used to fit respective standard species characteristics. Results demonstrated that F. gigantica is more pathogenic than F. hepatica, mostly due to its bigger size. Fasciola gigantica shows a delayed development of 1-2 weeks regarding both biliary phase and beginning of egg laying, with the respective consequences on the biochemical marker profile modifications in both the acute and chronic periods. A review on the physiopathogenicity by F. gigantica compared to that by F. hepatica is made. A biochemical marker baseline for human infection by F. gigantica is proposed to help physicians and health officers in F. gigantica human endemic areas.