Cylindrospermopsin (CYN) is a cyanobacterial toxin that induces a range of genotoxic indicators in a variety of models. The possible involvement of the tumor suppressor protein p53 in cylindrospermopsin-induced gene expression was examined in cultured human dermal fibroblasts and the human hepatocellular carcinoma cell line HepG2. After 6 h of exposure to CYN, concentration-dependent increases in mRNA levels were observed for the p53 target genes CDKN1A, GADD45, BAX, and MDM2, indicating an early activation of p53. After 24 h, relative mRNA levels for these genes remained elevated. Accumulation of p53 protein occurred after longer exposures in the HepG2-derived cell line C3A. Data suggest that cylindrospermopsin induces stress responses that result in the activation of the p53 transcription factor.