Background: RNA-RNA interactions, central to many biological processes, are often mediated by various secondary structural elements of the RNA. In the context of single-stranded RNA viruses such as Dengue virus (DENV) and other flaviviruses, such RNA-RNA interactions may be the key to switching between translation and replication. DENV (serotypes 1-4) is the causative agent of Dengue fever (DF), Dengue hemorrhagic fever (DHF), and Dengue shock syndrome (DSS). Each of the DENV serotypes is further classified into several genotypes having varying degrees of pathogenicity and virulence. One of the conserved features of DENV and other flaviviruses is the presence of complementary sequences in the 5'and 3'-untranslated regions (UTRs) that participate in long-range RNA-RNA interactions leading to the circularization of the genome. We hypothesized that the differences in secondary structures (and the corresponding three-dimensional orientation) of the 5' and 3' UTRs of the DENV RNA genome may underpin differences in virulence and pathogenicity of the different genotypes. Currently, there is no global scale analysis of DENV genomes correlating the RNA secondary structure with pathogenicity and virulence.Methods & Materials: Towards this end, we have curated the NCBI database for full length genomes of DENV and classified them according to their respective genotypes. Using mFOLD, we derived the putative RNA secondary structures of the 5'-end of the RNA genome (encompassing the 5' UTR, the capsid hairpin (cHP), and the 5'-cyclization sequence (5' CS)) and the final 106 nucleotides of the 3'-UTR (comprising the 3'-SL and 3'-CS). Comparative analysis of the secondary structure elements of different genotypes was done using in-house software packages. We have also performed comparative analysis of these RNA structural elements across the serotypes.Results: Our work has led to the observation of subtle but significant RNA secondary structure variations among not only the serotypes but within genotypes of a given serotype. Conclusion:By carrying out an extensive global analysis of DENV genomic RNA secondary structure we were able to correlate serotype and genotype specific RNA secondary structural elements and their possible role in pathogenicity and virulence.