Zika virus infection has emerged in Latin America as an important threat due to its association with GuillainBarré syndrome, which can lead to deaths, and microcephaly in newborn babies. Cases of fatal Zika virus infection are rare and misunderstood. The spectrum of clinical disease remains uncertain and considering the rapidly evolving epidemics of this new arbovirus in Latin America, it deserves further detailed assessment. Here, we describe four well documented fatal cases of Zika virus infection in Tolima, Colombia. Between Oct 2 and Oct 22, 2015, four febrile patients attended Tolima’s Hospitals in the central region of Colombia. Patients were a 2-year-old girl, a 30-year-old woman, a 61-yearold man, and a 72-year-old woman, with 2–6 previous days with fever. The infant girl also had dehydration, somnolence, hepatomegaly, mucosa haemorrhage, and thrombocytopenia, evolving to respiratory distress, disseminated intravascular coagulation, and shock. The 30-year-old woman had exanthema in upper and lower limbs, severe thrombocytopenia, and leukopenia, evolving in 10 days to intracerebral and subarachnoid haemorrhages, sepsis, acute respiratory failure, seizures, and shock. The older man had myalgias and arthralgias, with dehydration, mucosa haemorrhage, also evolving to respiratory distress, acute coronary syndrome, and shock. This patient’s history included high blood pressure under medication control. The older woman presented with abdominal pain, vomiting, dehydration, somnolence, and thrombocytopenia, evolving to acute respiratory failure and shock. This patient’s history included diabetes mellitus type 2 under control with insulin. In all four patients, giving the endemicity of the zone, dengue fever or chikungunya were suspected. All patients presented with anaemia (haemoglobin range 90–120 g/L), three of them with leukopenia. The 30-year-old woman had leukocytosis, and all but the older man had severe thrombocytopenia (<14 000 platelets per mL). Despite medical management at the intensive care unit, all of four patients died. The infant girl died 24 h after admission (5 days after symptoms began); the 30-year-old woman died after 10 days (12 days after symptoms began); the 61-year-old man at 24 h (7 days after symptoms begun), and the 72-year-old woman in less than 24 h (48 h after symptoms began). In all these cases, RT-PCR for dengue (including tissues), anti-dengue IgM, and NS1 ELISA and western-blot tests were negative. In the 61-year-old man, IgM for chikungunya was positive. IgM for Leptospira spp was negative in all cases. Finally, in all patients RT-PCR for Zika virus was positive, confi rmed at the Colombia national reference laboratory. In the infant girl and 30-yearold woman, necropsy revealed probable acute leukaemias (lymphoblastic and myeloid, respectively). In the 61 yearold man, necropsy showed ischaemic lesions in the brain with areas of necrosis in the liver and of systemic infl ammatory response in the spleen. In this patient, RT-PCR of tissues was positive for Zika virus. In the 72-year-old woman, necropsy showed oedema and ischemic lesions in brain. From Sept 22, 2015, to March 19, 2016, there were 58 838 cases of Zika virus infection in Colombia ( 2 3 6 1 l a b o r a t o r yc o n f i r m e d , 49 211 diagnosed by clinical criteria, and 7266 suspected); nevertheless before the current report, only one previous fatal case has been described, from our group in Colombia. Before the current outbreak in Latin America, Zika virus was not linked to deaths, but as of Nov 28, 2015, the Brazil Ministry of Health has also reported three deaths associated with Zika virus infection (two in adults and one in a newborn baby). These cases call attention to the need for evidence-based guidelines for clinical management of Zika, as well as the possible occurrence of atypical and severe cases (including possibly congenitally-related microcephaly). Based in our first case report, such guidelines have been considered and suggested by the European Centre for Disease Control in its recent Rapid Risk Assessment.