This is the first report of the largest epidemic of dengue hemorrhagic fever (DHF) virus infection (2006) with IgM-confirmed cases from Karachi, Pakistan. Medical records of 172 IgM-positive patients were reviewed retrospectively for demographic, clinical and laboratory data. Patients were categorized into dengue fever (DF) and DHF according to the WHO severity grading scale. The mean ± SD age of the patients was 25.9 ± 12.8 years, 55.8% were males and the hemoconcentration was recorded in a small number of patients [10 (7.0%)]. Male gender [odds ratio (OR) = 14.7, P = 0.003), positive history of vomiting (OR = 4.3, P = 0.047), thrombocytopenia at presentation (OR = 225.2, P < 0.001) and monocytosis (OR = 5.8, P = 0.030) were independently associated with DHF, but not with DF. Five cases (2.9%) had a fatal outcome, with a male-to-female ratio of 1:4. Three were from a pediatric group (<15 years). Pulmonary hemorrhages, disseminated intravascular coagulation and cerebral edema preceded death in these patients. The results have highlighted significant findings, such as adult susceptibility to DHF, pronounced abdominal symptoms and lack of hemoconcentration at time of presentation in the study population. These findings may play an important role in the case definitions of future studies from this part of the world.