La Reunion island in the South West Indian Ocean is now endemic for dengue followingthe introduction of dengue virus serotype 2 (DENV-2) cosmopolitan-I genotype in 2017. DENV-2infection causes a wide spectrum of clinical manifestations ranging from flu-like disease to severedengue. The nonstructural glycoprotein 1 (NS1) has been identified as playing a key role in denguedisease severity. The intracellular NS1 exists as a homodimer, whereas a fraction is driven towardsthe plasma membrane or released as a soluble hexameric protein. Here, we characterized the NS1glycoproteins from clinical isolates DES-14 and RUN-18 that were collected during the DENV-2epidemics in Tanzania in 2014 and La Reunion island in 2018, respectively. In relation to hepa-totropism of the DENV, expression of recombinant DES-14 NS1 and RUN-18 NS1 glycoproteins wascompared in human hepatoma Huh7 cells. We observed that RUN-18 NS1 was poorly stable inHuh7 cells compared to DES-14 NS1. The instability of RUN-18 NS1 leading to a low level of NS1secretion mostly relates to lysine residues on positions 272 and 324. Our data raise the issue of theconsequences of a defect in NS1 stability in human hepatocytes in relation to the major role of NS1 inthe pathogenesis of the DENV-2 infection.