Background In most countries engaged on the last mile towards malaria elimination, residual transmission mainly persists among vulnerable populations represented by isolated and mobile (often cross-border) communities. These populations are sometimes involved in informal or even illegal activities. In regions with Plasmodium vivax transmission, the specific biology of this parasite poses additional difficulties related to the need for a radical treatment against hypnozoites to prevent relapses. Among hard-to-reach communities, case management, a pillar of elimination strategy, is deficient: acute malaria attacks often occur in remote areas, where there is limited access to care, and drugs acquired outside formal healthcare are often inadequately used for treatment, which typically does not include radical treatment against P. vivax . For these reasons, P. vivax circulation among these communities represents one of the main challenges for malaria elimination in many non-African countries. The objective of this article is to describe the protocol of the CUREMA study, which aims to meet the challenge of targeting malaria in hard-to-reach populations with a focus on P. vivax. Results CUREMA is a multi-centre, international public health intervention research project. The study population is represented by persons involved in artisanal and small-scale gold mining who are active and mobile in the Guiana Shield, deep inside the Amazon Forest. The CUREMA project includes a complex intervention composed of a package of actions: (1) health education activities; (2) targeted administration of treatment against P. vivax after screening against G6PD deficiency to asymptomatic persons considered at risk of silently carrying the parasite; (3) distribution of a self-testing and self-treatment kit (malakit) associated with user training for self-management of malaria symptoms occurring while in extreme isolation. These actions are offered by community health workers at settlements and neighbourhoods (often cross-border) that represent transit and logistic bases of gold miners. The study relies on hybrid design, aiming to evaluate both the effectiveness of the intervention on malaria transmission with a pre/post quasi-experimental design, and its implementation with a mixed methods approach. Conclusions The purpose of this study is to experiment an intervention that addresses both Plasmodium falciparum and P. vivax malaria elimination in a mobile and isolated population and to produce results that can be transferred to many contexts facing the same challenges around the world.