In search for possible differences, we herein discovered the cellular ERGIC-53 lectin to be crucial for HBV viral particle release but dispensable for HBV spherical SVP secretion. ERGIC-53 is an ER export receptor for a limited number of glycoproteins and cycles between the ER, the ERGIC and the cis-Golgi through COPII and COPI-dependent pathways [42,49,50,53]. Its cytosolic tail contains an ER exit motif that binds to Sec24, the COPII cargo adaptor for anterograde transport, while an adjacent motif interacts with COPI to mediate the retrograde transport [50]. In-line with this, our IF studies showed that the trafficking of ERGIC-53, i.e., its export out of the ER was impaired upon the silencing of Sec24A. Mammalian cells contain four Sec24 isoforms that can be structurally and functionally divided into two subclasses, Sec24A/B and Sec24C/D. Interestingly, we found that the closely related Sec24B isoform failed to compensate for the loss of Sec24A and did not interfere with proper ERGIC-53 trafficking. Consistent with this, previous in vitro COPII budding assays and peptide-binding analyses revealed that all four Sec24 isoforms can, in principle, recognize ERGIC-53, though Sec24A turned out to be the most important isoform guiding the anterograde trafficking of the lectin [46,54]. Together, our results implicate that both the HBV envelope and cellular ERGIC-53 are selective clients of the Sec24A isoform.