Background: High TIL may confer better prognosis to TNBC patients and may interfere with trastuzumab (T) benefit in HER2-positive breast cancer (BC) patients. Here, we investigated the effect of TIL on BC patient outcome with respect to immunohistochemical subtypes and treatment. Methods: Intratumoral mononuclear infiltrates were assessed as % of stromal area under low magnification on whole routine sections of 2613 breast carcinomas. Three different cut-offs (c/o) for high/low TIL were used (50%, 35% and 25%). Subtyping revealed 948 Luminal A, 615 Luminal B, 477 Luminal-HER2, 246 HER2-enriched, and 327 TNBC tumors. Patients had been treated in the frame of 4 prospective trials with adjuvant anthracycline-based chemotherapy in the pre- and post-T era. T was administered sequentially for 1 year. Results: High TILs were present in 3.5%, 6.5% and 11.5% of all tumors, using the 50%, 35% and 25% c/o, respectively, and were subtype specific. Using the 35% c/o, high TIL were significantly more frequent in TNBC (13.8%), HER2-enriched (11.8%) and Luminal-HER2 (9.2%) than in Luminal B (5.7%) and Luminal A (1.8%) tumors (p < 0.0001). No significant TIL effect was observed on the outcome of patients with Luminal A and B tumors. High TIL, at all c/o, conferred decreased risk for relapse in patients with TNBC (e.g. 35% c/o, HR = 0.37, 95% CI 0.15-0.90, Wald’s p = 0.030) and Luminal-HER2 (e.g. 25% c/o, HR = 0.41, 95% CI 0.21-0.82, p = 0.011), but not with HER2-enriched tumors. Among all HER2-positive patients, a significant T benefit was noticed for those with low TIL (35% c/o, HR = 0.61, 95% CI 0.44-0.85, p = 0.003), but not for those with high TIL tumors; non-T treated patients with high TIL performed better than those with low TIL (HR = 0.56, 95% CI 0.36-0.87, p = 0.009), but this effect was insignificant among T treated patients. No interaction between T and TIL was found. Similar results were obtained for all TIL c/o, in distinct test and validation sets within the entire cohort. Conclusions: In the context of operable BC, high TIL is a favorable prognosticator in patients with TNBC and HER2-positive tumors. In the latter, high TIL does not seem to specifically predict for T benefit upon sequential T administration.