Objectives: To report the performance of a screening program for undiagnosed HCV infections in the general population of one Italian region. Methods: The Marche region, central Italy, provided organized free HCV screening for the resident population born between 1969 and 1989, from July 2023 to December 2025. People with known liver disease or HCV treatment were excluded, and those eligible were invited by letter to access the blood draw. After a positive anti-HCV test, a reflex HCV-RNA test was performed on the same sample. The investigated outcomes were extension, uptake, HCV-RNA detection rate, and positive predictive value (PPV) of the anti-HCV test. Potential predictors of an infection diagnosis were investigated through multivariable analyses. Results: Over 30 months, 412,897 individuals were invited (93.6% extension), and 48,596 participated (11.8% uptake). Positive tests were 308 for anti-HCV (0.63%) and 42 for HCV-RNA (0.09% detection rate), with a relatively low PPV of the anti-HCV test (13.6%), which increased in males (15.2%) and individuals born in specific foreign countries (>20%). Multivariate analyses confirmed a higher risk of a positive HCV-RNA test for males (adjusted odds ratio—OR: 2.21; 95%CI 1.45–3.38) and those born in Moldova, Ukraine, and Pakistan (adjusted ORs between 10 and 15; p ≤ 0.001). Conclusions: The low detection rate was consistent with other Italian studies, suggesting that a combination of opportunistic recruitment and tailored pathways is required for high-risk groups in order to achieve the WHO HCV elimination targets. Future analyses should assess linkage-to-care and therapy compliance to evaluate the long-term cost–benefit ratio.
Martellucci et al. (Thu,) studied this question.