Antigenic evolution of human influenza A viruses facilitate the virus to escape pre-existing immunity through abrupt drift with structural alterations in antigenic epitopes. Therefore, annual seasonal influenza epidemics lead to an estimated ~3 to 5 million cases of severe illness and 250,000 to 500,000 deaths which can potentially increase to million or higher in major pandemic years 1, 2. Especially, overcrowded areas associated with poverty in low-income countries are major reservoir of influenza virus and has higher incidence of influenza related hospitalizations 3, 4. Influenza viruses belong to the family Orthomyxoviridae and their genome comprises eight single-stranded RNA segments with negative polarity that translate at least 12 proteins 5. The segmented genome allows them to exchange or reassort RNA segments between viruses when the host is co-infected with two or more influenza strains 6. Since the genomic reassortment is a natural event, it can generate novel strains with enhanced pathogenicity which facilitates crossing of species barriers and thereby contributes to major influenza pandemics at unpredictable intervals 7, 8. Two envelope glycoproteins: hemagglutinin (HA) and neuraminidase (NA) play most important roles in viral infection: attaching the virions with host receptors and releasing progeny virions from infected cells 9. Mutations at critical positions of these two surface proteins may alter the viral antigenic characteristics 10. Besides, mutations in the internal proteins have impact on virus life cycle including replication, packaging, release or cellular apoptosis and can generate a new variant with enhanced virulence and infectivity 11. The replication complex components PB2 and M1 proteins are recognized as an imperative determinant of replication and host range restriction 12, 13. The PB1-F2 protein dictates pro-apoptotic function and NS1 protein coupled with the activation of anti-apoptotic mechanisms allows viral replication 14, 15. Thus, elevated replication rate or provocation of anti-apoptotic systems result in higher viral production that can exceed host immune response, increase infectivity with more severe and transmissible disease consequences.Although the average antigenic evolution of H1N1pdm is much slower than H3N2, it has the most fatal outcome since last decade compared to other seasonal viruses 16. The first influenza pandemic of 21st century occurred in 2009 by swine-origin influenza A/H1N1pdm leading to an estimated 150,000-575,000 deaths worldwide 17, and has been regarded to the densely populated settings as it also observed in devastating Spanish flu during the World War I 18, 19. In the post-pandemic period, this virus continues to circulate throughout the world as a seasonal human influenza virus. Recently, an outbreak of influenza A/H1N1pdm occurred in overpopulated India where around one third of the global slum inhabitants reside, infected more than 35,000 cases and the death toll rose to 2335 as of 21 April, 2015 20, 21. As Bangladesh is one of the most overpopulated country and comprised of around 10 thousand slums with highly compromised sanitation and economic condition, various infectious diseases emerge each year with substantial morbidity and mortality rates 22, 23. Several studies thus far conducted focusing the prevalence of influenza infections in slums, however, molecular epidemiology of causative virus yet to be explored 24, 25. This study therefore aimed to investigate the genomic profile of 2013 A/H1N1pdm and A/H3N2 strains isolated from an urban slum of Dhaka, Bangladesh. We describe here (i) genetic relatedness of eight gene segments of slum isolates to those of contemporary Bangladeshi strains as well as globally circulating strains; (ii) mutations in antigenic epitopes in HA and NA genes compared to vaccine strains; and (iii) amino acid differences among internal genes of the viruses that might have impact on virus pathogenesis.?