Dr PB is supported by Carlos Chagas Foundation for the Advancement of Science of the State of Rio de Janeiro (FAPERJ), https://www.faperj.br/, grant numbers [E-26/200.935/2022] and [E-26/211.565/2019]; by DECIT, www.saude.gov. br/sctie/decit, grant number 25000.072811/2016-19; and by CNPQ, https://www.gov.br/cnpq/pt-br, grant number 311562/2021-3. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Introduction: Acute febrile illnesses (AFI) are a frequent chief complaint in outpatients. Because the capacity to investigate the causative pathogen of AFIs is limited in low- and middle-income countries, patient management may be suboptimal. Understanding the distribution of causes of AFI can improve patient outcomes. This study aims to describe the most common etiologies diagnosed over a 16-years period in a national reference center for tropical diseases in a large urban center in Rio de Janeiro, Brazil. Methods: From August 2004-December 2019, 3591 patients > 12 years old, with AFI and/or rash were eligible. Complementary exams for etiological investigation were requested using syndromic classification as a decision guide. Results. Among the 3591 patients included, endemic arboviruses such as chikungunya (21%), dengue (15%) and zika (6%) were the most common laboratory-confirmed diagnosis, together with travel-related malaria (11%). Clinical presumptive diagnosis lacked sensitivity for emerging diseases such as zika (31%). Rickettsia disease and leptospirosis were rarely investigated and an infrequent finding when based purely on clinical features. Respiratory symptoms increased the odds for the diagnostic remaining inconclusive. Conclusions: Numerous patients did not have a conclusive etiologic diagnosis. Since syndromic classification used for standardization of etiological investigation and presumptive clinical diagnosis had moderate accuracy, it is necessary to incorporate new diagnostic technologies to improve diagnostic accuracy and surveillance capacity.