The tumour suppressor gene p53 is the most commonly mutated gene in solid tumours. Although less common in haematological malignancies, 10–15% of B‐cell chronic lymphocytic leukaemia (B‐CLL) cases carry a p53 mutation. Recently, the compound P53‐dependent reactivation and induction of massive apoptosis (PRIMA‐1) has been shown to induce cytotoxic effects and apoptosis in human tumour cells by restoration of the transcriptional activity of mutated p53. This is believed to be mediated by a change in the conformation of mutated p53 protein, restoring DNA binding and activation of p53 target genes. We studied the effects of PRIMA‐1 and commonly used anti‐leukaemic drugs on B‐CLL cells from 14 patients with and without hemizygous p53 deletion. Cells obtained from peripheral blood or bone marrow were exposed to PRIMA‐1 and fludarabine alone or in combination. PRIMA‐1 showed cytotoxic effects on B‐CLL cells from samples with and without hemizygous p53 deletion. Furthermore, conventional B‐CLL drugs were less effective in cell samples with hemizygous p53 deletion and the response depended on the size of the p53 deleted clone. Finally, we found evidence for synergistic and additive effects of PRIMA‐1 in combination with fludarabine.