The increased transmission and geographic spread of dengue fever (DF) and its most severe presentations, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), make it one of the most important mosquito-borne viral disease of humans. Four distinct serotypes of dengue viruses are transmitted to humans through the bites of the mosquitoes. Currently there is no vaccine or antiviral drug against DV infections. Cross-protection between dengue virus serotypes is limited and antibody dependent enhancement (ADE) contributes significantly to the severity of the disease. The major challenge is to induce a broad durable immune response against all four serotypes of dengue virus simultaneously while avoiding the possible exacerbation of risk of developing the severe forms of disease through incomplete or modified responses. In order to address this worldwide concern, we present a synthetic consensus (SynCon) human codon optimized DNA vaccine that elicits immunity against all four dengue serotypes. We cloned consensus DIII domain of E protein from all serotypes and expressed them as a single open reading frame in a mammalian expression vector, called pDV-U-DIII (dengue-vaccine universal). In mice, this dengue-universal construct elicits significant level of anti-DIII antibody that neutralizes all four dengue subtypes and prevents cell death induced by dengue infection. This is the first SynCon DNA vaccine that provides tetravalent immunity against all four serotypes of dengue virus.