Calcium aluminate cement (CAC) has been proposed as an alternative to mineral trioxide aggregate (MTA), but its biological behavior remains underexplored. This study evaluated the cytotoxicity, genotoxicity, and proinflammatory gene expression of fibroblasts exposed to CAC formulations containing zinc oxide or bismuth oxide with different proportions of calcium chloride, in comparison with MTA. Fibroblasts were cultured with CACz (25% ZnO + 2.8% CaCl₂), CACb (25% Bi₂O₃ + 2.8% CaCl₂), CACb+ (25% Bi₂O₃ + 10% CaCl₂), or MTA; non-exposed cells served as controls. Cytotoxicity was assessed by fluorescence microscopy and MTT viability assays at 24 h and 72 h, while genotoxicity was evaluated by the comet assay at 24 h. Gene expression of COL-1, TNF-α, IL-1β, IL-6, and MMP-9 was examined by RT-qPCR at 72 h. Data were analyzed using the Kruskal-Wallis test and the Student-Newman-Keuls post hoc test (α = 0.05). Cell viability did not differ among groups at 24 h, but was higher for CACb+ at 72 h (p < 0.05). DNA damage levels were similar across groups (p > 0.05). For gene expression, no significant differences were observed for COL-1, IL-1β, or TNF-α. All cements upregulated IL-6 compared with control (p < 0.05), with the highest levels in MTA and the lowest in CACb+. CACb+ increased MMP-9 expression (p < 0.05), while CACz showed the lowest levels. Within the limits of this study, CAC formulations with additives were not genotoxic or cytotoxic, and their biological behavior was composition-dependent, with CACb+ demonstrating the most favorable profile by enhancing fibroblast viability and extracellular matrix remodeling potential.