Therapeutic proteins like human interferon alpha 2 generally possess short serum half-lives due to their small size, hence rapid renal clearance, and susceptibility to serum proteases. Chemical derivatization, such as addition of polyethylene glycol (PEG) groups overcomes both problems, but at the expense of greatly decreased bioactivity. We describe a new method that yields biologically potent interferon alpha 2b (IFN alpha 2) in high yields and with increased serum half-life when expressed as arabinogalactan-protein (AGP) chimeras in cultured tobacco cells. Thus IFN alpha 2-AGPs targeted for secretion typically gave 350-1400-fold greater secreted yields than the non-glycosylated IFNa2 control. The purified AGP domain itself, was not immunogenic when injected into mice and only mildly so when injected as a fusion glycoprotein. Importantly, the AGP-IFN alpha 2 chimeras showed up to a 13-fold increased in vivo serum half-life while the biological activity remained similar to native IFN alpha 2. The use of arabinogalactan glycomodules may provide a general approach to the enhanced production of therapeutic proteins by plants.