Detection of Plasmodium falciparum parasites in patients with malaria necessitates drawing blood, which increases the risk of accidental infections and is poorly accepted in communities with blood taboos. Thus, non-invasive, cost-effective malaria tests that minimize the need for blood collection are needed. Plasmodium falciparum histidine-rich protein II (PfHRP II) levels in plasma and saliva were compared in malaria-positive and -negative patients in Ghana. Plasma and saliva obtained from 30 thick-film positive and 10 negative children were evaluated for PfHRP II by ELISA. Among the 30 children with positive blood smear, 16 (53%) were PfHRP II positive in plasma and 13 (43%) had PfHRP II positive saliva. The sensitivity of PfHRP II detection was 53% for plasma and 43% for saliva. The specificity was 100% with no false positive for both plasma and saliva when compared with blood smear. Thus, rapid detection of PfHRP II antigen in saliva may be a useful non-invasive and cost-effective malaria diagnostic technique.