Purpose: The unfolded protein response (UPR) and ER stress play a significant role in determining the outcome of DENV infection. The activation of UPR is cell-type dependent. There are no data available on the effect of DENV infection on the UPR in human primary cells. We conducted in vitro experiments on human primary macrophages to identify the effect of DENV on the IRE1α-XBP1 and PERK-eIF2α-ATF pathway. Methods & Materials: Human peripheral blood monocytes were differentiated to macrophages and infected with DENV 16681 at a multiplicity of infection 1. Cells were harvested, lysed and western blots were performed using antibodies against PERK, eIF2α, peIF2α, and ATF at selected time points. Cells were harvested and RNA extraction was done to identify XBP1 RNA by qRT-PCR at selected time points. Secreted viruses from cells were quantified by a qRT-PCR assay and infectious virus levels were identified using a plaque assay. Secreted TNFα and IFNα were measured using a functional assay. GSK2606414 and 4μ8c were used to inhibit the PERK and IRE1α-XBP1 arms, respectively. Tunicamycin, an ER stress inducer was used as the control. Results: A non-significant increase in ATF4 protein was seen at 12 hours post infection (p.i.) with no change in ATF4 mRNA levels at 6 and 12 hours p.i. in macrophages. Activation of the PERK arm although minimal was seen early at 6 hours p.i. and a robust IRE1α-XBP1 arm activation was seen at 48 hours p.i.. DENV infection increased the XBP1t and XBP1s levels with an increase in the XBP1s/XBP1t ratio. Inhibition of the IRE1α-XBP1s pathway resulted in a significant reduction in secreted and infectious virus from macrophages in addition to reduced secretion of TNFα and IFNα levels. PERK arm inhibition did not have an effect on secreted virus or secreted IFNα. However, secreted TNFα levels were reduced by PERK inhibition. Conclusion: Activation of PERK and IRE1α-XBP1 arms were time-dependent. The IRE1α-XBP1 pathway was pro-viral and chemical inhibition of XBP1 splicing resulted in low DENV secretion and reduced TNFα and IFNα secretion from primary human macrophages. DENV activates the pro-viral IRE1α-XBP1 pathway preferentially over the PERK arm in primary macrophages.