Human natural interferon-beta (HuIFN-beta) was administered through different routes (intravenous [i.v.], intramuscular [i.m.], and subcutaneous [s.c.]) and its distribution in lymph and plasma was evaluated. After i.v. (bolus) administration the lymph/plasma ratio was about 0.35 but it significantly increased (11-fold) after i.m. administration. Addition of human albumin (ALB) to the IFN solution did not favor IFN absorption through the lymphatics. On the other hand, addition of ALB improved IFN absorption through the lymphatics after s.c. administration. These results are interesting because they clarify why IFN-beta can exert immunomodulatory activities in spite of very low plasma levels.