As the predominant etiological agent of the common cold, rhinoviruses (RV) have a substantial economic impact and contribute to severe respiratory complications in immune compromised and asthmatic individuals. While zinc ions have been previously shown to have an inhibitory effect upon RVs, clinical trials using zinc products have produced conflicting results, and the lack of a known mechanism of zinc inhibition has stymied therapeutic development. We find that extracellular exposure alone, of both major and minor group RVs to zinc chloride (ZnCl) and zinc gluconate (ZnG), is sufEicient to profoundly decrease infectivity. The infectivity of other picornaviruses is not decreased in the presence of Zn compounds, suggesting that Zn-mediated virus inhibition is RV specific. Other metal cations similar to Zn have not demonstrated RV inhibition. Zn-based inhibition of RV is independent of pH, is effected within minutes, and is dampened at lower temperatures. Furthermore, whereas EDTA and pyrithione can chelate Zn to prevent inhibition of RV, these chelators cannot reverse the Zn- based inhibition. Exposure of Zn-treated RV to pyrithione can dramatically increase the degree of inhibition. In addition, preliminary competition assay and infectious center plaque assay data suggest that this mechanism is not related to the virus-cellular receptor interaction. Rhinovirus mutants selected for resistance to Zn have amino acid changes on the capsid surface and interior. These results demonstrate that Zn can inhibit RVs through a novel extracellular mechanism that is not dependent upon replication and assembly processes within the infected cell. Elucidating the mechanism of this extracellular inhibition should provide novel insight into the virucidal capabilities of Zn that may enable the optimization of small molecule therapeutics to treat rhinovirus infections.