IntroductionViral hepatitis stands accountable for approximately 1.34 million deaths worldwide, with the number of fatalities steadily growing with time. This is partly due to the various genotypes of hepatitis C virus and having no vaccination developed yet. However, a paradigm shift in the epidemiology of hepatitis C was notable due to the emergence of direct-acting antiviral drugs. Nevertheless, related literature in the Saudi context still requires further investigations to improve strategies and interventions targeting HCV in Saudi Arabia.ObjectivesThis study was conducted to estimate the lifetime prevalence of hepatitis C virus (HVC) in Riyadh, KSA, and assess factors associated with HCV that include demographics and co-morbidities.Methods and MaterialsThis cross-sectional study was conducted at a tertiary healthcare facility, located in Riyadh. The patients' database was searched for data regarding hepatitis C screening and treatment in a time window from 2017 to 2022. The study sample was composed of all individuals screened for or diagnosed with hepatitis C infection in the previously mentioned settings.ResultsOur sample included a total of 16,690 participants, 929 of which had positive test results (5.6%; 95% CI: 5.2-5.9%), with the rate being significantly higher in post-COVID-19 years due to a decreased number of tests performed. Positive test results were associated with male gender (43.4%), chronic kidney disease (11.8%), diabetes mellitus (34.9%), and hypertension (35%). Adjusted odds ratios (aOR) were obtained, with male gender (aOR: 2.47), widowed (aOR: 7.8) or divorced (aOR: 2.07) marital status, diabetes mellitus (aOR: 1.97), and hypertension (aOR: 2.87). Singles were found to be at lower risk of infection (aOR: 0.38). For each additional year of the study window, the odds of infection increased by 1.18.ConclusionBetween 2017 and 2022, The HCV RNA positive cases were estimated to be 5.6%. Several risk factors were identified, including male gender, being widowed or divorced, and having diabetes mellitus, and hypertension. These results underline several opportunities to improve public health efforts and clinical practice in Saudi Arabia. That will further enhance the agenda targeting the burden of HCV in the country.Clinical TrialNot applicable.