Human class I transplantation antigens are cell-surface-expressed molecules composed of one glycosylated, membrane-integrated heavy chain and one nonglycosylated, water-soluble subunit, beta 2-microglobulin (beta 2m). We have examined the intracellular transport of the two subunits by microinjecting mRNA into Xenopus laevis oocytes. Beta 2m, translated in oocytes, was transported and secreted into the medium in the absence of heavy chains whereas heavy chains were retained in the endoplasmic reticulum if not cotranslated with beta 2m. In the presence of beta 2m, heavy chains resisted digestion by endoglycosidase H (Endo H), suggesting that beta 2m promotes the transport of heavy chains from endoplasmic reticulum to the Golgi compartment. Pulse-chase experiments confirmed this notion. The possibility that heavy chains aggregate irreversibly when synthesized in the absence of beta 2m was ruled out and it is demonstrated that performed heavy chains will become transported once beta 2m is available. It is suggested that intracellular transport is controlled by structural features that are part of the transported polypeptide. If so, beta 2m but not heavy chains may possess such features.