Conventional cancer therapy, such as ã-irradiation and cytotoxic drugs, acts via DNA damage-induced apoptosis and inhibition of proliferation. Major problems with conventional cancer therapy are that only subgroups of patients respond favourably to a given treatment, and that side effects often limit the dose efficiency of the treatment. The immune cells of the patient may for instance commit to apoptosis as a result of the therapy. It is therefore a constant search for modulators of DNA damage responses to improve such cancer therapies. To identify potential modulators it is important to have good read out systems. One of the key proteins down stream of the DNA damage checkpoint is the tumour suppressor p53. Upon DNA damage, the transcription factor p53 is stabilized and activated to affect target genes involved in growth arrest, DNA repair and apoptosis. Testing the efficacy of a given modulator of DNA damage responses may therefore include analysis of p53 expression and activity. Vitamin A plays an important role in the immune system to protect against infection, and deficiency of this vitamin affects more than 100 million children throughout the world. One of the important metabolites of vitamin A is retinoic acid (RA), and RA is a well known regulator of cell proliferation and differentiation of numerous cell types, including lymphoid cells. The purpose of the present study was to explore a possible role of RA as a modulator of DNA damage responses in lymphocytes, and in particular we wished to elucidate the effects of RA on regulation of p53 expression in this process. Freshly isolated lymphocytes from healthy blood donors were stimulated with mitogens and treated with RA prior to induction of DNA damage by ã-irradiation. The amount of apoptotic cells was measured by flow cytometry, and Western blot analysis was performed to identify p53 expression. We were able to show that although RA stimulates and inhibits the proliferation of normal T - and B cells, respectively, DNA damage-induced apoptosis was inhibited in both cell types. The effect of RA was particularly strong in TPA-stimulated T cells, and we could show that apoptosis induced by both ã-irradiation and the cytotoxic drug doxorubicin was inhibited. Importantly, we also showed that the RA-mediated inhibition of DNA damage-induced apoptosis was associated with reduced expression of p53, indicating that RA affects the DNA damage checkpoint. The physiological implications of the present results in that the vitamin A status of a cancer patient receiving chemotherapy or irradiation might influence the effect of the treatment, both by affecting the killing of malignant lymphocytes, as well as to protect the immune system from unwanted damage during irradiation or chemotherapy.