The simultaneous detection of antigen and antibody was originally described for the early detection of the human immunodeficiency virus (HIV). The same approach was applied to detect the hepatitis C virus (HCV). The aim of this work was to use the antigen and antibody combination assay for the detection of HCV and HIV infections in expatriates in Eastern Saudi Arabia. The study group (N = 875) included expatriate workers of both sexes who were undergoing mandatory pre-employment testing. Detection of anti-HCV antibodies, HCV core antigen, HCV viral RNA, HIV antigens and antibodies was conducted using commercially available kits. Of the 875 samples that were screened for HCV-specific antibodies, four (0.46%) tested positive (two from Pakistan, one from India, and one from the Philippines) and two (0.23%) were equivocal (one from Egypt and one from Nepal). All four samples that were positive for HCV-specific antibodies also tested positive using HCV RNA assay and the HCV antigen-antibody combination assay. The two samples that were equivocal tested positive using the HCV RNA assay and the HCV antigen-antibody combination assay. Of the 875 samples that were tested for HIV antibodies, only one (0.11%) sample gave repeatedly positive results. The same sample also tested repeatedly positive using the HIV combination assay. These results were subsequently confirmed by HIV western blot assay. Our study indicates that the addition of antigen detection to the screening of HCV and HIV may lower the risk of transmission of these viruses in the host country and contribute to the overall control of HCV and HIV in Saudi Arabia.