Nickel-based resins have long been used in biochemical studies for the purification of His-tagged proteins, but their potential in the isolation of histidine-derived small molecules has not been investigated to date. Many agriculturally-important mycotoxins incorporate histidine residues, as do natural products from both plants and bacteria. Here, a highly-selective solid-phase extraction method is described for the purification of histidine-derived natural products using the insoluble nickel salt Ni-3(PO4)(2). This led to the highly-selective binding and elution of two natural products, meleagrin and gartryprostatin C, from two fungal strains, Penicillium chrysogenum and Aspergillus sclerotiorum, respectively. A simple protocol involving binding, washing with water and methanol, and elution with methanolic acetate buffer, gave 65-75% recovery of both compounds directly from crude extracts of the two fungi. The procedure can easily be used as part of a multi-step isolation process in combination with HPLC to yield the purified alkaloids.