p53 family proteins include p53 tumor suppressor, p63, and p73. Despite the high similarity in structure and function with p53, p63, and p73 function in tumor suppression is still controversial. Here, we show that TAp73alpha, a transcriptionally active p73 isoform, is able to synergize p53 tumor suppressor function in thyroid cancer cells. Indeed, depletion of p73 by small interfering RNA in thyroid cancer cells resulted in a reduced transcriptional activity of p53. Ectopic coexpression of both p53 and TAp73alpha in thyroid cancer cells resulted in increased transcription and tumor suppressor function compared with p53 or TAp73alpha alone, as well as in increased p53 protein levels. The enhancing effect of TAp73alpha on p53 activity is Mdm2 dependent because it is prevented by Mdm2 depletion by small interfering RNA. At least two mechanisms may explain the interference of TAp73alpha with p53 function. First, in thyroid cancer cells, TAp73alpha inhibits the effect of p53 on Mdm2 induction by antagonizing p53 at the Mdm2 promoter level. Second, a TAp73alpha mutant (G264W), which is devoid of DNA binding capability, is still able to increase p53 protein levels by competing with p53 for Mdm2 protein binding. Taken together, these results indicate that in thyroid cancer cells, TAp73alpha is able to increase p53 protein level and function by interfering with Mdm2-mediated p53 degradation. These results may be useful for designing gene therapies aimed at restoring a normal p53 function in thyroid cancer cells.