Exit of soluble secretory proteins from the endoplasmic reticulum (ER) can occur by receptor‐mediated export as exemplified by blood coagulation factors V and VIII. Their efficient secretion requires the membrane lectin ER Golgi intermediate compartment protein‐53 (ERGIC‐53) and its soluble luminal interaction partner multiple coagulation factor deficiency protein 2 (MCFD2), which form a cargo receptor complex in the early secretory pathway. ERGIC‐53 also interacts with the two lysosomal glycoproteins cathepsin Z and cathepsin C. Here, we tested the subunit interdependence and cargo selectivity of ERGIC‐53 and MCFD2 by short interference RNA‐based knockdown. In the absence of ERGIC‐53, MCFD2 was secreted, whereas knocking down MCFD2 had no effect on the localization of ERGIC‐53. Cargo binding properties of the ERGIC‐53/MCFD2 complex were analyzed in vivo using yellow fluorescent protein fragment complementation. We found that MCFD2 is dispensable for the binding of cathepsin Z and cathepsin C to ERGIC‐53. The results indicate that ERGIC‐53 can bind cargo glycoproteins in an MCFD2‐independent fashion and suggest that MCFD2 is a recruitment factor for blood coagulation factors V and VIII.