Malaria remains the highest cause of morbidity and mortality in Ghana and the rest of sub-Saharan Africa. Early diagnosis is therefore essential to treatment and eradication of the disease. This study was therefore designed to find out the efficacy of the First Response PfHRP2 malaria antigen test kit which promises to give reliable test results in diagnosing P. falciparum malaria as microscopy, the gold standard, since most of the malaria cases in our part of the world is caused by Plasmodium falciparum. The survey was carried out on a total number of 354 patients on who clinicians had requested for malaria test in four selected health facilities within the Cape Coast metropolis of Ghana. For each of these patients, both thick and thin blood films for microscopy, and rapid diagnostic test (RDT) were done using blood obtained from a finger prick or venipuncture. Of the 354 patients, 66 (18.6%) positive malaria cases were recorded for both microscopy and RDT. Fifty two (52) patients were diagnosed as truly positive for P. falciparum malaria by the rapid diagnostic test and 278 (78.5%) were diagnosed as truly negative. Paired sample T-test showed a p-value of 0.85 at α= 0.05 indicating no significant difference between microscopy and the RDT in the diagnosis of Plasmodium falciparum malaria. A prevalence rate of 18.6% was recorded for malaria cases with 78.8% occurrence of Plasmodium falciparum. The RDT recorded sensitivity and specificity of 79% and 95% respectively. The study lends credence to the fact that the rapid diagnostic test kit has comparable level of accuracy with microscopy and hence can be used in rapid screening of malaria but not as a complete substitute for microscopy in malaria diagnosis.