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• No study has assessed the clinical and biological features of chikungunya virus epidemics in French Guiana. • We performed the first study suggesting the use of a clinical score to differentiate dengue virus infection (DENV) from chikungunya (CHIKV) infection. • This is a topical theme as DENV and CHIKV epidemics recently occurred in India and Brazil. External validation of this score will thus be possible. • The study sample was relatively large (162 CHIKV patients versus 452 DENV patients). Only two other studies have compared CHIKV and DENV: a study conducted in Singapore included 117 CHIKV patients and 862 DENV patients, and a study conducted in Gabon included 270 CHIKV patients and 53 DENV patients. It should be noted that both of these studies reached contradictory conclusions. Chikungunya (CHIKV) and dengue viruses (DENV) are two arboviruses with epidemic potential and similar clinical presentations. The potential life-threatening risk associated with DENV justifies an immediate biological assessment and medical follow-up which may be delayed for CHIKV. To compare the clinical variables that would help differentiate patients infected with CHIKV or DENV, and then to compute a predictive score. Retrospective case-control study comparing CHIKV-infected patients diagnosed by RT-PCR in 2014 with patients infected with DENV diagnosed by positive NS1 antigen test in 2013. Children aged < 15 years and pregnant women were excluded. Clinical and biological variables were compared, and a multivariate analysis was performed. A clinical score was developed using the β coefficients to differentiate the infections. Over the study period 168 patients infected with CHIKV were compared with 452 patients with DENV. The clinical variables independently associated with CHIKV was joint and back pain, and those associated with DENV were headache, muscle pain, nausea/vomiting, diarrhea, and hemorrhagic signs. The clinical score had 98% sensitivity for DENV and a ROC curve of 0.96. These two infections have a similar clinical presentation but the use of the proposed clinical score during the acute phase of the disease would make it possible to identify cases of DENV during a CHIKV epidemic to suggest adequate patient management. [ABSTRACT FROM AUTHOR]