Co-infection with Hepatitis C Virus (HCV) is a common occurrence in Human Immunodeficiency Virus (HIV)-positive patients and an increasing cause of morbidity and mortality. Little is known however of the burden or the natural history of these infections or their interactions in most parts of sub-Saharan Africa, where both viruses are endemic. In this study a total of 1500 people aged 11 months to 76 years referred to the serology unit of Royal Victoria Teaching Hospital between the months of July to December 2003 were evaluated for anti-HIV, anti-HCV and CD4+ T-cell count and compared with the subjects' socio-demographic and risk factors. HIV and HIV/ HCV seropositive persons who consented to a follow-up study were age and sex matched with HIV and HCV seronegative control subjects and followed for 18 months with biannual monitoring of trends in CD4 count against a possible HIV or HCV seroconversion of the seronegative control subjects. The overall prevalence of antibodies to HIV and HCV was 6.7% (101/1500) (Cl, 5.6-8.2) and 2.1% (31/1500) (95 % CI, 1.4-2.9) respectively. HIV rates in asymptomatic adults were 3.6 %( 43/1189) (OR: 0.16; Cl: 0.13-0.28) and 1.0 %( 12/1189 (OR: 0.16; Cl: 0.08-0.34) for HCV. HIV/HCV co-infections rate was 0.6% among all the subjects sampled and 8.6% in HIV positive persons. The HIV rate in this study is twice the UNAIDS/WHO estimate for the country and twice the numbers of women than men were infected with HIV at a comparatively younger age, while males 55 years and over had higher HIV rates than those below 35. HCV and HIV/HCV coinfection was more commonly associated with males than females. This study showed that Hepatitis C serotype 2 is the most prevalent type in the country and was predominantly associated with HIV-1, and suggests that HCV serotype 2 spread earlier than serotypes 1 and 3. The mean CD4 count of apparently healthy males and females was 489/μl and 496/μl respectively, while the mean CD4 count at diagnosis (CD4dx) of HIV, and HIV/HCV persons was 310 cells/μl and 306 cells/μl respectively. Only about half of the apparently healthy population had CD4 counts of 500 cells and over (51 %), while 1.1 % (15/1377) had counts below 200 cells per microlitre for no explained reasons. HN/HCV co-infected person recorded a lower CD4 count at diagnosis than HIV alone infected persons and also a more significant decline in CD4+ than HIV infected alone persons. The study shows that high HIV rates were independent of the educational status of the individual, while history of sexually transmitted diseases, high income earning and involvements in polygamous marriages were all significant risk factors for HIV, HCV and HIV/HCV co-infection. Female circumcision, knowledge and use of condoms, blood oath, histories of blood transfusion and wife inheritance were not associated with HIV or HCV transmission. The study found an HIV incidence rate of 1.4% (4/288) during the 18 months follow-up period and identified Sexually Transmitted Diseases (STDs) as the associated risk factor. There is need for a new CD4+ staging in the country based on the population within the country and the initiation of a large scale longitudinal study to elucidate the risk factors associated with HCV in the country. The study has provided baseline data on CD4 and its trends in co-infected persons and also a baseline on the distribution and epidemiological pattern and associated risk factors of co-infection between HIV and HCV in the country. It has also determined the incidence of HIV and its associated risk factors in the country. The study has therefore contributed to our understanding of the natural history of these infections and provided an important frame work for possible intervention.