Abstract Background The aim of this analysis was to investigate the potential impact of Ki67 assay in a series of patients affected by early stage invasive lobular carcinoma (ILC) undergone surgery. Methods Clinical-pathological data were correlated with disease-free and overall survival (DFS/OS). The maximally selected Log-Rank statistics analysis was applied to the Ki67 continuous variable to estimate appropriate cut-offs. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed to assess the interaction between ‘pure’ or ‘mixed’ histology ILC and Ki67. Results At a median follow-up of 67 months, 10-years DFS and OS of 405 patients were 67.8 and 79.8 %, respectively. Standardized Log-Rank statistics identified 2 optimal cut-offs (6 and 21 %); 10-years DFS and OS were 75.1, 66.5, and 30.2 % (p = 0.01) and 84.3, 76.4 and 59 % (p = 0.003), for patients with a Ki67 21 %, respectively. Ki67 and lymph-node status were independent predictor for longer DFS and OS at the multivariate analysis, with radiotherapy (for DFS) and age (for OS). Ki67 highly replicated at the internal cross-validation analysis (DFS 85 %, OS 100 %). The STEPP analysis showed that DFS rate decreases as Ki67 increases and those patients with ‘pure’ ILC performed worse than ‘mixed’ histology. Conclusions Despite the retrospective and exploratory nature of the study, Ki67 was able to significantly discriminate the prognosis of patients with ILC, and the effect was more pronounced for patients with ‘pure’ ILC.