Due to the severity and the high risk of re-emergence of yellow fever, a disease caused by an arthropod-borne virus, the Democratic Republic of the Congo (DRC) has implemented an active surveillance program throughout the country since 2003 based on the involvement of healthcare structures located in the health areas. All suspected clinical cases compatible with Yellow fever disease, including fever and jaundice, were notified to the Ministry of Health and rapidly tested for Yellow fever infection. A total of 652 suspected YF cases were detected through the program, of which only less than 5% tested positive for YFV. In order to investigate other causative pathogens, we previously investigated Chikungunya, dengue, and hepatitis (A, B, C and E) virus infections retrospectively in available samples [1, 2]. We found 3.5% (n = 16/453), 0.4% (n = 2/453), 16.7% (72/432), 22.3% (n = 105/470), 2.3% (n = 9/379) and 10.4% (n = 38/365) which tested positive for Chikungunya, Dengue virus, HAV, HBV, HCV and HEV, respectively. Though these investigations associated 224 suspected yellow fever cases to a potential causative pathogen, many remained unidentified. Here, we investigated four human herpes viruses (HHVs) known to sometimes cause acute jaundice and which infect African populations at high prevalences: herpes simplex virus (HSV1 & HSV2), varicella-zoster virus (VZV), cytomegalovirus (CMV), and human herpes virus type 6 (HHV-6) [3, 4]. Indeed, the seroprevalence of HSV1, HSV2, and CMV are estimated to be 87%, 31%, and 82%, respectively [5–8]. The seroprevalence of VZV is variable across countries and studies in Africa (0–90%) [9]. Few data exist on the prevalence of HHV-6, but it can reach 100% in many regions of the world [10]. As these viruses typically establish a life-long persistent infection within specific tissues such as ganglia of the nervous system (HSV, VZV) and lymphoid tissue (CMV, HHV-6) [7] after primary infection, they undergo periods of dormancy during which viral replication and shedding is not observable. A resurgence of viral replication can occur at any time, and may be more likely following infection by a subsequent pathogen. Such co-infections could potentially be responsible for the clinical signs observed in these suspected yellow fever cases. Clinical manifestations are also diverse: HSV-1 causes blisters on the lips and HSV-2 is associated with similar blisters or sores on the genitals, CMV induces pneumonia and meningitis, VZV is responsible for Varicella (chickenpox) or herpes zoster (shingles) after reactivation, and HHV-6 is the cause of the common childhood illness exanthema subitum (also known as roseola infantum) [11, 12].