Innate immune cells are key player in immune response to influenza virus infection. Influenza infected monocytes exacerbate the disease pathology. However, monocytes differ in susceptibilities to influenza virus infection. Herein, susceptibilities of U937 and THP-1 monocytic cells to PR8 virus infection, the associated cellular factor- sialic acid (SA) receptor distribution and viral factor were determined. Moreover, amino acid sequences in hemagglutinin (HA) receptor binding domain (RBD) of PR8 virus that determine SA preferences were analysed. PR8 infected U937 cells express significantly higher numbers of nucleoprotein positive cells suggesting U937 cells being more susceptible to influenza virus than THP-1 cells. Lectin staining suggested similar pattern of SA receptor distribution in both cells. Interestingly, sequence analysis of RBD suggested their preferences for alpha 2,3 SA receptors suggesting RBD sequences are not always determining for SA preferences. Furthermore, the resistance barrier on THP-1 cells was overcome by H5N1 NS gene. In conclusion, the study demonstrated that decreased susceptibility of THP-1 cells to PR8 virus could not be related to the SA receptor distribution, and H5N1 NS gene was sufficient to determine tropism for THP-1 cells. Hence, mechanistic basis of NS gene on cell tropism and contribution of other internal genes remained to be determined.