Interferons (IFNs) play a crucial role in the host's immune response and other homeostatic control actions. Three IFN types and several IFN families within the types allow for a plethora of regulatory actions. The number of distinct IFN molecules is highest among type I IFNs and, in particular, within the IFN-α family. In pigs, there are 17 IFN-α subtypes with different antiviral activities and different expression profiles; however, no data are available about biological properties other than the antiviral effector activities. Therefore, 16 porcine IFN-α genes were cloned, expressed in mammalian Chinese hamster ovary cells, and characterized for antiviral, anti-inflammatory, and MHC-modulating activities at a pre-established level of 10 IU/mL. Antiviral activity: IFN-α2, -α5, -α9, and -α10 showed the highest level of activity in a pseudorabies virus yield reduction assay. On the contrary, little, if any, activity was shown by IFN-α3, -α7, -α13, -α4, and -α15. Anti-inflammatory activity: With the exception of IFNs-α2, -α7, -α9, and -α11, all IFN-α subtypes had significant anti-inflammatory control activity in an interleukin-8 (IL-8) yield reduction assay. Gene expression analyses showed that some IFN-α subtypes can significantly downregulate the expression of IL-8, tumor necrosis factor α (TNF-α), IL-6, Toll-like receptor 4 (TLR4), βD1, and nuclear factor-κB (NF-kB) genes, while maintaining or upregulating the expression of βD4. Immunomodulation: A significant upregulation of class I and/or class II MHC was induced by all the IFNs under study, with the exception of IFNs-α11, -α15, and -α16, which instead significantly downregulated class I MHC. Our results indicate that gene duplications in the porcine IFN-α family underlie diverse effector and regulatory activities, being therefore instrumental in host survival and environmental adaptation. This role of IFN-α could be founded on fine-tuning and regulation of pro- and anti-inflammatory control actions after exposure to both infectious and noninfectious environmental stressors.