Antidepressants differ greatly from class to class and within individual members of a class in terms of their adverse drug profile and their toxicity in acute overdose conditions. To reduce the use of animals, a number of in vitro tests are now under investigation to determine the acute toxicity of drugs. The objective of this study was to investigate fresh water proto, zoa Tetrahymena pyriformis with regard to the acute toxicity of antidepressants. The cytotoxic effects of a range of currently marketed antidepressants were evaluated using the MTT assay, and the IC50 values were determined for each. These IC50 values did not correlate with the FTI (Fatal Toxicity Index) values in humans. Thus it can be concluded that the Tetrahymena pyriformis cytotoxicity assay is a poor predictor in evaluating the acute toxicity of antidepressants in humans, which is in keeping with other in vitro methodologies using mammalian cells. It can be concluded that, in the absence of credible in vitro tests, acute toxicity in intact animals will continue to be the method for predicting the acute toxicity of antidepressants.