Background: Adenoid cystic carcinoma (ACC) is a salivary cancer with a variable disease course. Inoperable locally advanced, recurrent or metastatic ACC (LA-R/M-ACC) are its commonest manifestations. The disease course is typically indolent with patients remaining on surveillance for many years before initiating relatively ineffective systemic therapies. A sub-group of patients experience rapid disease progression and surveillance is not indicated. NOTCH gain-of-function mutation (NOTCH^gof) is well characterised, defining a genomic sub-group with shorter survival times. However, there remains a need to identify additional prognostic biomarkers to inform the clinical management of these patients. TP53 mutation (TP53^mt) has been proposed as a prognostic biomarker warranting further evaluation. Methods: Clinical-genomic data from 349 ACC patients with LA-R/M-ACC were included. 198 patients provided written informed consent to an ethically approved study, and a further 151 were identified through cBioPortal (MetTropsim, Cell, 2021). ACC tumour samples were evaluated by next-generation sequencing (NGS) for the presence of NOTCH^gof and TP53^mt. Kaplan-Meier analysis was performed, and p values calculated with the log-rank test, to calculate overall survival (OS) from inoperable LA or R/M disease for patients with either NOTCH^gof alone, TP53^mt alone or both NOTCH^gof/TP53^mt combined. Results: ACC tumours harboured NOTCH^gof in 14.0% (49/349) and TP53^mt in 13.8% (48/349) of cases, respectively. Co-occurrence of TP53^mt was identified in 16% of ACC tumours with NOTCH^gof (8/49), being in 2.3 % of all LA-R/M-ACC cases. Median OS from inoperable LA-R/M disease was significantly reduced for patients with co-occurrent NOTCH^gof/TP53^mt (n=8, 10.0 mo; 95% CI 8–12), followed by NOTCH^gof/TP53^wt (n=41, 15.2 mo; 95% CI 8–22), NOTCH^wt/TP53^wt (n=262, 58.6 mo; 95% CI 52–65) and NOTCH^wt/TP53^mt (n=40, 69 mo; 95% CI 13–125) (p=<0.001). TP53 alterations were available for functional classification in 33 patients and were classed as loss-of-function point mutations in 81.8% or truncating frameshift mutations in 18.2%. Truncating TP53^mt were mutually exclusive with NOTCH^gof. Although the smaller number in this group limits statistical power, patients with truncating TP53^mt had shorter OS from recurrence (15.9 mo; 95% CI 0-39) compared with other TP53^mt (51.0 mo; 95% CI 0-108; p=0.41). Conclusions: A subgroup of LA-R/M ACC patients with co-occurrent TP53^mt and NOTCH^gof were identified with significantly shorter OS from recurrence than either NOTCH^gof or TP53^mt alone. Truncating TP53^mt may have greater prognostic value than other TP53^mt in NOTCH^wt ACC. This study provides further evidence of the potential prognostic utility of some TP53 mutations in ACC and highlights groups of patients with aggressive disease who are potentially suitable for inclusion in therapeutic research programmes.