Background: Malaria is a major world health issue and its continued burden is due in part to difficulties in the diagnosis of the illness. The World Health Organization recommends confirmatory testing using microscopy based techniques or rapid diagnostic tests (RDT) for all cases of suspected malaria. In regions where Plasmodium species are indigenous there are multiple etiologies of fever leading to misdiagnoses especially in populations where HIV is prevalent and children. To determine the frequency of malaria infection in febrile patients over an 8 month period at the Regional Hospital in Bamenda Cameroon we evaluated the clinical efficacy of the Flourescence and Staining Technology (FAST) Malaria stain and ParaLens Advance(TM) microscopy system (FM) and compared it with conventional bright field microscopy and Giemsa stain (GS). Methods: Peripheral blood samples from 522 patients with a clinical diagnosis of "suspected malaria" were evaluated using GS and FM methods. A nested PCR assay was the gold standard to compare the two methods. PCR positivity sensitivity specificity positive predictive value (PPV) and negative predictive value (NPV) were determined. Results: Four hundred ninety nine samples were included in the final analysis. Of these 30 were positive via PCR (6.01%) with a mean PPV of 19.62% and 27.99% for GS and FM respectively. The mean NPV was 95.01% and 95. 28% for GS and FM respectively. Sensitivity was 26.67% in both groups and specificity was 92.78% and 96.21% for GS and FM respectively. An increased level of diagnostic discrepancy was observed between technicians based upon skill level using GS which was not seen with FM. Conclusions: The frequency of malarial infections confirmed via PCR among patients presenting with fever and other symptoms of malaria was dramatically lower than that anticipated based upon physicians' clinical suspicions. A correlation between technician skill and accuracy of malaria diagnosis using GS was observed that was less pronounced using FM. Additionally FM increased the specificity and improved the PPV suggesting this relatively low cost approach could be useful in resource limited environments. Anecdotally physicians were reluctant to not treat all patients symptomatically before results were known and in spite of a negative microscopic diagnosis highlighting the need for further physician education to avoid this practice of overtreatment. A larger study in an area with a known high prevalence is being planned to compare the two microscopy methods against available RDTs.