A cross-sectional study was conducted in the Peruvian Amazon to test the hypothesis that a reservoir of asymptomatic malaria parasitemic patients would form the basis for continuing malaria endemicity in the region. Active surveillance yielded a Plasmodium spp. slide-positive prevalence of 4.2% (43 of 1,023) and a polymerase chain reaction (PCR)-positive prevalence of 17.6% (144 of 819). Plasmodium vivax prevalence was 2.9% and 14.2% while Plasmodium falciparum prevalence was 1.3% and 2.6% by microscopy and PCR, respectively. Approximately two-thirds of slide-positive and one-fourth of PCR-positive people were symptomatic. Anemia was associated with slide positivity (P < 0.001) and PCR positivity for P. falciparum (P = 0.003). Sensitivity of field microscopy and agreement between field and reference laboratory microscopists were low, arguing for using PCR for epidemiologic investigation and malaria control. While these data confirm recent findings from the Brazilian Amazon suggesting that sufficient numbers of asymptomatic malaria parasitemic patients are present to form a persistent reservoir for continuous reinfection within the Peruvian Amazon region, these results also indicate that clinical immunity in human populations can be driven in malaria-endemic regions that do not have high intensity malaria transmission.