Endometrial cancer (EC) treatment changed substantially with the introduction of molecular classification. There is a paucity of data regarding the added value of L1CAM in patients with p53 aberrant tumours. The present study aimed to analyse the prognostic value of L1CAM associated with p53 aberrant EC. Patients with EC treated between 2010 and 2016 were retrospectively evaluated. Patients included in this analysis must have reviewed high-grade histologies (endometrioid grade 3, serous, clear cell, carcinosarcoma, mixed and undifferentiated). Samples were subjected to immunohistochemistry for L1CAM and p53. Recurrence-free survival (RFS) and overall survival (OS) were analysed by the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was performed for multivariable analysis. From 2010 to 2016, 464 patients met the inclusion criteria. Patients with p53 wild type and L1CAM negative (p53wt/L1CAMneg) corresponded to 13.6% (59 patients) of the population, p53 wild type and L1CAM positive (p53wt/L1CAMpos) to 11.7 % (51 patients), aberrant p53 and L1CAM negative (p53ab/L1CAMneg) to 32.9% (143 patients) and aberrant p53 with L1CAM positive (p53ab/L1CAMpos) to 41.8% (182 patients). In univariate and multivariate analysis, compared to patients with p53wt/L1CAMneg, the presence of p53wt/L1CAMpos, p53ab/L1CAMneg and p53ab/L1CAMpos was statistically associated with a worse RFS (HR 2.02; HR 2.20 and HR 2.99, respectively) and OS (HR 2.39; RH 2.31 and RH 2.94, respectively). In the present analysis of a high histological risk population, stages I–IV, we observed that the presence of p53ab/L1CAMpos was associated with a worse RFS and OS when comparing p53wt/L1CAMneg patients. Patients with L1CAMpos had the same worse prognosis as p53ab tumours.