The mineral stability of two bentonites was studied in the presence of pyrite concentrate to simulate the possible reactions between the bentonite barrier used in a high-level nuclear waste (HLW) repository and host rock containing up to 5 wt.% of admixed pyrite. Smectite was the only bentonite mineral affected by pyrite treatment under the experimental conditions used. Bentonites reacted differently with pyrite due to the different nature of the smectites. The distinct crystal chemistry of the smectites controlled by the composition of the parent rocks influenced the smectite surface properties (cation exchange capacity and layer charge distribution) which resulted in a different response of the bentonites to pyrite treatment. A partial transformation of the original smectites into H-smectites represented the initial stage of smectite destabilization on acid attack. Rising non-equivalent isomorphous substitution in the octahedral sheets of the smectites enhanced smectite reactivity and thus the reaction between bentonite and pyrite, causing lower stability of the bentonite containing high-charge smectite.