Malaria is one of the leading causes of infectious disease in travelers returning from the tropics. The diagnosis of malaria is typically performed by examining Giemsa-stained thick and thin peripheral blood smears, which is time consuming, labor intensive, and requires high levels of proficiency. Alternatively, loop-mediated isothermal amplification (LAMP) is a new molecular method, which is rapid, sensitive, and requires less capital equipment and technological training. We conducted a retrospective study comparing two formats of a commercial LAMP assay (Meridian gene malaria [M] and malaria Plus [MP]) versus reference microscopy on archived blood specimens ( = 140) obtained from unique returning travelers suspected of having malaria. Discrepant results were resolved by either repeat testing or a laboratory developed ultrasensitive real-time PCR method. On initial testing, the Meridian gene M and MP kits had sensitivities of 97.3% (95% confidence interval [CI], 90.7 to 99.7%) and 100.0% (95.1 to 100.0%) and specificities of 93.8% (84.8 to 98.3%) and 91.5% (81.3 to 97.2%), respectively, versus reference microscopy. We project a significant cost reduction in low prevalence settings where malaria is not endemic with LAMP-based malaria screening given the excellent negative predictive value achieved with LAMP.