Alterations in TP53 have been described in many cancer types including hematological neoplasms. We aimed at comparing TP53 mutations (mut) and deletions (del) in a large cohort of patients with hematological malignancies (n = 3307), including AML (n = 858), MDS (n = 943), ALL (n = 358), CLL (n = 1148). Overall, alterations in TP53 were detected in 332/3307 cases (10%). The highest frequency was observed in ALL (total: 19%; mut+del: 6%; mut only: 8%; del only: 5%) and AML (total: 13%; mut+del: 5%; mut only: 7%; del only: 1%), whereas TP53 alterations occurred less frequently in CLL (total: 8%) and MDS (total: 7%). TP53 mutations were significantly more frequent in patients ≥ 60 vs < 60 years in AML (9% vs 2%, P < 0.001) and ALL (12% vs 6%, P < 0.001). TP53mut+del had a significant negative impact on overall survival in all entities, whereas differences were observed regarding TP53mut only or TP53del only: TP53mut only impacted survival in AML (36 vs 9 months, P < 0.001) and MDS (65 vs 19 months, P < 0.001), TP53del only in CLL (not reached vs 64 months, P = 0.008) and MDS (65 vs 24 months, P = 0.011). As substantial differences between the entities are observed regarding correlation to age and survival, we suggest evaluation of both TP53 deletion and mutation status.