A 74 year old woman from Karpathos, Greece presented for evaluation of splenomegaly. IS months before, when the splenomegaly was first noted, she had no constitutional symptoms and denied previous malaria. Treated in Athens with methotrexate for presumed lymphoma, she developed quartan fever which resolved when methotrexate was stopped. Blood smears were negative. In our clinic, systemic symptoms and signs of illness were absent, except for a spleen extending 14 cm below the costal margin. She had a hemoglobin of 11.8, polyclonal hypergammaglobulinemia, and a negative U/A. Five blood smears obtained over 14 days were negative for Plasmodium, Plasmodium genus-specific RT-PCR for 18S rRNA, species-specific oligonucleotide hybridization, and sequencing of PCR bands indicated/1, malariae parasitemia. IFA showed that the patient had high titered antibodies to P. malariae (1/64,000). One month after treatment with 3 days of chloroquine, the spleen had returned to normal size. At one year followup, she had gained 20 pounds, hemoglobin normalized and hypergammaglobulinemia resolved. On further investigation, the patient's older sister said that at age 3, the patient had malaria that was never treated Malaria transmission was eliminated in Greece by 1949. Therefore, the patient likely had P. malariae infection for at least 47 years, possibly >70 years. The recrudescence of symptomatic malaria after methotrexate treatment, in the presence of high levels of anti-parasite antibodies, suggests that cellular immunity controlled this patient's chronic infection. Malaria should be considered as the cause of asymptomatic splenomegaly in patients from formerly malarious regions, even in the absence of detectable parasitemia.