Abstract : Microcystins (MCs), produced by freshwater cyanobacteria, are hepatotoxins involved in numerous cases of human and animal intoxications. Ingestion is the major pathway of human exposure. Among almost 90 variants described, MC-LR is the most frequent and the most toxic variant on which MCs risk assessment has been set up. In order to characterize the hazard for human ingestion, we chose to study and compare absorption and toxicity of two variant, MC-LR and MC-RR, on a human intestinal cell line (Caco-2). The two variants, even with are known for their difference in acute toxicity. . We showed that, on the contrary to hepatocytes, both variants were uptaken equally by Caco-2 cells. Moreover, our results suggest a active efflux of MCs from Caco-2 cells. Finally, comparing MC-LR and MC-RR toxicity at a pangenomic scale elicited dissimilarity in cell responses with a larger effect of MC-LR including on oxidative stress, cell cycle regulation, stress of the endoplasmic reticulum and protein degradation. So, differences on the mechanism of toxicity between both variants are suggested. Thereby, our work highlights the need of toxicity studies on other variants than MC-LR in order to improve MCs risk assessment.