The authors report the difficulties faced in diagnosing and managing dengue fever in a 16-year-old boy suffering from glucose-6-phosphodehydrogenase deficiency and thalassemia intermedia 2 months after splenectomy. Prolonged fever, hepatomegaly, decrease in hematocrit were observed. Negative blood cultures, normal procalcitonin and persistent fever despite broad-spectrum antibiotics decreased the possibility of bacterial sepsis. Platelet count decreased to 58,000/μL on the day of defervescence and dengue IgM serology was positive. The course of dengue fever can be very different if underlying thalassemia, splenectomy and/or G-6PD deficiency are present.