Implemented as one arm of the malaria control program in French Guiana in the early 1990s, our laboratory has since established in vitro profiles for parasite drug susceptibility to a panel of eight antimalarials for more than 1,000 Plasmodium falciparum isolates from infected patients. The quinine-doxycycline combination was introduced in 1995 as the first-line drug treatment against uncomplicated P. falciparum malaria, replacing chloroquine, and the first-line drug combination was changed to the artemether-lumefantrine combination in 2002. Resistance to chloroquine declined 5 years after it was dropped in 1995 as the first-line drug, but unlike similar situations in Africa, there was a rapid halt to this decline. Doxycycline susceptibility substantially decreased from 2002 to 2005, suggesting parasite selection under quinine-doxycycline drug pressure. Susceptibility to mefloquine decreased from 1997 onward. Throughout the period from 1994 to 2005, most isolates were sensitive in vitro to quinine, amodiaquine, and atovaquone. Susceptibility to amodiaquine was strongly correlated with that to chloroquine and to a lesser extent with that to mefloquine and halofantrine. Susceptibilities to mefloquine and to halofantrine were also strongly correlated. The Guyana Shield currently has the highest malaria rates in South America and is the only geographical area in the Americas where Plasmodium falciparum infection is diagnosed more frequently than P. vivax infection. In French Guiana, P. falciparum accounts for 60 to 70% of the 3,000 to 5,000 malaria cases reported every year (3). Malaria occurs in isolated geographical foci situated along the rivers in the Amazonian forest, and the population has little specific immunity. Malarial control involves spraying insecticides over the coastal region, where approximately 80% of the population resides, and using bed nets, an evidence-based drug policy, and deploying health services in remote endemic areas to provide prompt treatment by public primary health centers and/or private practitioners.As in the neighboring countries of the Amazon basin (36), P. falciparum is multidrug resistant, with failures documented for chloroquine (18), the amodiaquine/sulfadoxine-pyrimethamine combination (22), halofantrine (9, 19), chloroquine-proguanil (19), and even quinine (6). In the last decade, the drug policy in French Guiana has been based on both an in vivo assessment of therapeutic efficacy and longitudinal monitoring of in vitro drug susceptibility. In 1995, the quinine-doxycycline combination was recommended as the first-line treatment. It was replaced by the artemether-lumefantrine combination in 2002.Monitoring drug resistance is particularly important in this region, where illegal gold-mining activities in the malaria endemicity areas are associated with erratic consumption of antimalarials and frequently with self-medication, unclear compliance to recommended regimens, and the formulation and use of illegally imported molecules of unknown quality, which contribute to the select...