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Nowadays, the safety of parabens as pharmaceutical preservatives is debated. Recent studies investigated their interference with the oestrogen receptors, nevertheless their carcinogenic activity was also proved. That was the reason why the re-evaluation of the biocompatibility and antimicrobial activity of parabens is required using modern investigation methods. We aimed to test the cytotoxic, antifungal and antibacterial effect of parabens on Caco-2 cells, C. albicans , C. parapsilosis , C. glabrata , E. coli , P. aeruginosa and S. aureus . Two complex systems (glycerol-Polysorbate 20; ethanol-Capryol PGMC™) were formulated to study-with the MTT-assay and microdilution method, respectively-how other excipients may modify the biocompatibility and antimicrobial effect of parabens. In the case of cytotoxicity, the toxicity of these two systems was highly influenced by co-solvents and surfactants. The fungi and bacteria had significantly different resistance in the formulations and in some cases the excipients could highly modify the effectiveness of parabens both in an agonistic and in a counteractive way. These results indicate that with appropriate selection, non-preservative excipients can contribute to the antimicrobial safety of the products, thus they may decrease the required preservative concentration.