Nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, has recently been demonstrated to block protein transport from the endoplasmic reticulum (ER) to the Golgi complex. The ER to Golgi transport is primarily operated by the ER-Golgi intermediate compartment (ERGIC). We examined the effect of NDGA on the ERGIC, focusing on the distribution of its marker ERGIC53. In control cells ERGIC53 was distributed to vesicular tubular structures corresponding to the ERGIC as well as to the ER and the cis-Golgi, reflecting its cycling between these compartments. Upon treatment of cells with NDGA, ERGIC53 was rapidly accumulated in the Golgi and undetectable in the ER and the ERGIC. Prolonged incubation of cells with the drug, however, caused redistribution of ERGIC53 and resident Golgi proteins to the ER. Thus, it is likely that NDGA has dual effects on ERGIC53 cycling; the initial accumulation in the Golgi may be caused by blocking its retrieval from the cis-Golgi to the ER/ERGIC, while the delayed redistribution to the ER may occur through a pathway induced by the drug that is different from the COPI-dependent pathway.