Hemizygous TP53 deletion is an adverse risk factor in multiple myeloma (MM) but its relationship with p53 protein expression is unclear. We investigated 105 newly diagnosed myeloma patients and correlated nuclear p53 protein immunoreactivity with TP53 deletion status, myeloma-associated genetic risk factors and survival. Fluorescence in situ hybridisation (FISH) detected hemizygous TP53 deletions in 13 (12%) patients while immunohistochemistry detected nuclear p53 protein expression in 12 (11%). Ten (77%) of the 13 del(TP53) cases expressed nuclear p53 protein while 10 (83%) of the 12 nuclear p53 immunoreactive cases had hemizygous TP53 deletions. Hemizygous TP53 deletion and p53 protein expression were strongly correlated (P < 0.001). The overall survival of patients with p53 protein expression was significantly shorter than that of patients without p53 expression (P < 0.001). A multivariate analysis including other myeloma-associated genetic risk factors confirmed p53 expression as an independent risk factor for survival. Our data indicate that nuclear p53 protein expression, detected by a widely available immunohistochemical method, is strongly associated with TP53 deletion and an adverse clinical outcome for MM.