Background Here, we assessed the presence of intrahepatic follicular helper T-cells (T_FH) in a cohort of consecutive genotype 1 (G1) chronic hepatitis C (CHC) patients comprising non-responders (NRs), relapsers (RRs) or those with sustained virological response (SVR) to pegylated interferon and ribavirin, and tested their relation with the response to antiviral treatment. Methods A total of 78 patients with G1 CHC (30 SVR, 15 RR and 33 NR), comparable for sex, age, viral load and fibrosis were evaluated by immunohistochemistry for liver content of PD1+Bcl6+ T_FH cells. The number of T_FH cells in the immunostained sections was counted out of five representative high-power microscopic fields (400x) relative to areas involved by the inflammatory infiltrate. IL28B rs12979860 and rs8099917 polymorphisms were also evaluated. Results The absolute number of liver T_FH progressively increased from NR to RR to a maximum in SVR patients (14.2 ±12.5 versus 24.5 ±12.5 versus 59.2 ±27.1; P<0.001). The mean absolute number of liver T_FH was 24.3 ±21.1 in 18 TT polymorphism patients, 31.7 ±29.5 in 43 TC and 47.8 ±27.8 in 17 CC ( P=0.01). SVR was achieved in 27/35 (77.1%) of patients with T_FH ≥28 and in only 3/43 (6.9%) of those with T_FH<28. Similarly, 15/17 (88.2%) CC patients achieved SVR, compared with 15/61 (24.6%) TT/ TC subjects. With the combination of T_FH at the threshold of 28 and the rs12979860 polymorphism, the ability to predict SVR strongly increased. Conclusions In G1 CHC patients, T_FH cells are present in the hepatic inflammatory infiltrate. Their amount is proportional to the ultimate likelihood of SVR, with a progressive increase from NR to RR to SVR. Quantification of T_FH cells in the liver biopsy of these patients adds useful prognostic information.