Human rIL-2, expressed and purified from Escherichia coli, is currently being tested as an anticancer therapeutic agent. Some of the patients undergoing clinical trials with rIL-2 have developed antibodies to rIL-2. We describe a chemical modification of rIL-2 that reduces its immunogenicity. rIL-2 has been chemically modified with a water soluble polymer, monomethoxy polyethylene glycol (PEG). This covalent conjugate PEG-rIL-2 has enhanced solubility and extended in vivo circulation. Attachment of PEG to rIL-2 reduces its immunogenicity when tested in rabbits and in mice. Ag-specific IgG antibody titers were 100 to 1000-fold lower when PEG-rIL-2 was used as the Ag, compared to rIL-2. In a long term study, 7 of 10 rabbits injected with PEG-rIL-2 had no Ag-specific IgG antibody response. In these seven rabbits, the in vivo behavior of the injected PEG-rIL-2 remained essentially unchanged after repeated immunizations. PEG-rIL-2 injected before rIL-2 injections, immunosuppressed the antibody response to rIL-2 in rabbits. The maintenance of the systemic exposure of PEG-rIL-2 after repetitive dosing is related to its decreased immunogenicity. Thus, the PEGylation (covalent attachment of PEG) of rIL-2-enhances its potential as an anticancer therapeutic.