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Dengue virus (DENV) circulates in human and sylvatic cycles. Sylvatic strains are both ecologically and evolutionarily distinct from endemic viruses. Although sylvatic dengue cycles occur in West African countries and Malaysia, only a few cases of mild human disease caused by sylvatic strains and one single case of dengue hemorrhagic fever in Malaysia have been reported. Here we report a case of dengue hemorrhagic fever (DHF) with thrombocytopenia (13000/µl), a raised hematocrit (32% above baseline) and mucosal bleeding in a 27-year-old male returning to Spain in November 2009 after visiting his home country Guinea Bissau. Sylvatic DENV-2 West African lineage was isolated from blood and sera. This is the first case of DHF associated with sylvatic DENV-2 in Africa and the second case worldwide of DHF caused by a sylvatic strain. Author Summary: Dengue viruses are mosquito borne pathogens that cause up to 100 million infections annually. Dengue viruses circulate in either humans or non-human primates in two separate cycles: human and sylvatic. All four different serotypes infect humans causing frequent epidemics and severe disease, including hemorrhagic fever. Until a few years ago, viruses circulating in the sylvatic cycle had been associated with asymptomatic to mild disease only in humans. For example, retrospective analysis of human serum samples collected in Nigeria from the 1960s proved that sylvatic dengue was able to cause an outbreak of dengue fever in human population. Recently a case of DHF in Asia was linked to sylvatic DENV-2 (strain DKD811) infection. Here, we report the first case of DHF associated with sylvatic DENV-2 infection in Africa caused by a complete different lineage of the virus. All these events underscore the need to be vigilant about the re-emergence of DHF from sylvatic cycles. [ABSTRACT FROM AUTHOR]