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<p>Abstract</p> <p>Background</p> <p>Information on the epidemiology of malaria is essential for designing and interpreting results of clinical trials of drugs, vaccines and other interventions. As a background to the establishment of a site for anti-malarial drugs and vaccine trials, the epidemiology of malaria in a rural site in central Ghana was investigated.</p> <p>Methods</p> <p>Active surveillance of clinical malaria was carried out in a cohort of children below five years of age (n = 335) and the prevalence of malaria was estimated in a cohort of subjects of all ages (n = 1484) over a 12-month period. Participants were sampled from clusters drawn around sixteen index houses randomly selected from a total of about 22,000 houses within the study area. The child cohort was visited thrice weekly to screen for any illness and a blood slide was taken if a child had a history of fever or a temperature greater than or equal to 37.5 degree Celsius. The all-age cohort was screened for malaria once every eight weeks over a 12-month period. Estimation of Entomological Inoculation Rate (EIR) and characterization of <it>Anopheline </it>malaria vectors in the study area were also carried out.</p> <p>Results</p> <p>The average parasite prevalence in the all age cohort was 58% (95% CI: 56.9, 59.4). In children below five years of age, the average prevalence was 64% (95% CI: 61.9, 66.0). Geometric mean parasite densities decreased significantly with increasing age. More than 50% of all children less than 10 years of age were anaemic. Children less than 5 years of age had as many as seven malaria attacks per child per year. The attack rates decreased significantly with increasing cut-offs of parasite density. The average Multiplicity of Infection (MOI) was of 6.1. All three pyrimethamine resistance mutant alleles of the <it>Plasmodium falciparum dhfr </it>gene were prevalent in this population and 25% of infections had a fourth mutant of <it>pfdhps</it>-A437G. The main vectors were <it>Anopheles funestus </it>and <it>Anopheles gambiae </it>and the EIR was 269 infective bites per person per year.</p> <p>Conclusion</p> <p>The transmission of malaria in the forest-savanna region of central Ghana is high and perennial and this is an appropriate site for conducting clinical trials of anti-malarial drugs and vaccines.</p>