Melanoma is an aggressive form of skin cancer with high occurrence in the United States. Interferon alpha2b (IFNalpha2b/IFNalpha2) has been used in high doses to treat melanoma. However, problems associated with small molecule therapeutics such as with IFN treatment include small molecular size, degradation by serum proteases, and rapid kidney clearance. Pegylation has been used to overcome this, but in itself possesses a host of other issues such as decrease receptor binding, nonspecific chemical derivatization, low overall yields, and additional purification steps. An alternative to this produces IFN as arabinogalactan fusion proteins in plant cells. These IFN analogs bind to IFN receptors and follow the IFN-induced Janus Kinase 1-signal transducers and activators of transcription signaling pathway. Here, we show that these fusion proteins of higher molecular weight also cause similar growth inhibition and affect cell cycle distribution in melanoma cells M92-047 and SK MEL-28. Lastly, the fusion proteins increased translation of 2'5'-oligo adenylate synthetase and Protein Kinase R, known IFN-induced proteins, showing similar downstream signaling as native recombinant IFNalpha2.