Background/Objectives: Phosphatidylinositol (PI) species are bioactive lipids implicated in liver fibrogenesis. Hepatitis C virus (HCV) relies on host lipid metabolism for infection. The relationship between serum PI profiles, chronic HCV, and liver injury remains incompletely defined. Methods: Fourteen PI species were quantified by direct flow injection–tandem mass spectrometry (FIA–MS/MS; triple quadrupole) in serum from 178 patients with chronic HCV at three time points: before treatment and at weeks 4 and 12 after starting direct-acting antiviral (DAA) therapy. Results: At baseline, PI 34:1, 36:1, and 36:3 were
higher in patients with ultrasound-diagnosed cirrhosis than in those without, whereas PI 38:4, 40:5, and 40:6 were lower. In non-cirrhotic patients, PI 36:3, 36:4, 38:3, 38:4, and 38:5 increased, while PI 40:5 and 40:6 declined at weeks 4 and 12 after therapy start. In cirrhosis, viral cure was not associated with changes in PI species. By the end of therapy, cirrhotic patients showed higher PI 36:3 and lower PI 38:4 than non-cirrhotic patients. Genotype 3a was associated with lower PI 38:3, 38:4, and 38:5; the reduction in PI 38:4 persisted to the
end of therapy. Across time points, most PI species did not correlate with routine markers of liver injury or inflammation. Conclusions: HCV cure remodels the serum PI profile in non-cirrhotic patients. These findings suggest that altered PI profiles are primarily linked to HCV infection, supporting a role for PI lipids in viral propagation.