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The pathogenesis of dengue hemorrhagic fever (DHF) is not well known, but the role of host factors has been suggested. The level of immunoreactive circulating and cell‐generated tumor necrosis factor alpha (TNFα) was studied in 35 patients with DHF; its relationship with virus isolation and/or genome detection by reverse transcription polymerase chain reaction (RT‐PCR) and specific antibodies were detected by hemagglutination inhibition (HI). Large variation of TNFα plasma levels was obtained in dengue‐infected patients at the same stage of the disease and at the same day after infection. Most of the patients (14 out of 17 patients) who displayed augmented spontaneous in vitro production of TNFα by heparinized whole‐blood culture compared with controls also had elevated levels of TNFα in the plasma. The TNFα values in lipopolysaccharide and phytohemagglutinin heparinized whole‐blood cultures were not higher in patients than in controls, but low TNFα levels were obtained in three out of 30 patients. An inverse correlation was observed between spontaneous in vitro TNFα production and viral replication, which raises the issue of the antiviral effect of TNFα in dengue infection. The results do not support the hypothesis of the role of antibody‐dependent enhancement giving rise to increased viremic titers and production of TNFα in patients. The present study demonstrates the activation of the TNFα‐producing cells in dengue‐infected patients and suggests further investigation to define the mechanism and the role of TNFα in the pathogenesis of dengue virus infection. J. Med. Virol. 54:210–218, 1998.© 1998 Wiley‐Liss, Inc.