The currently ongoing outbreak of Monkeypox virus in many non-endemic countries around the world has also raised concerns about the safety of plasma-derived medicinal products. Based on what is known about the poxvirus family, i.e., that members are exceedingly large and carry a lipid envelope, effective removal and inactivation by plasma product manufacturing processes is expected. For the widely used solvent-detergent treatments, however, poxviruses have been reported as potentially being a bit more resistant. The current investigation sought to verify poxvirus inactivation by Triton X-100-based solvent-detergent treatment. For vaccinia virus, a model closely resembling monkeypox virus, we measured fast inactivation to the assay detection limit, i.e., reduction of infectivity greater than 4 log10 within 10–20 min. As use of Triton X-100 will, based on environmental concern around its release, be restricted, a physicochemically virtually identical alternative, Nereid, was also tested, and found fully equivalent.