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Simple Summary: While tumor-associated macrophages (TAMs) are known to be associated with a poor prognosis in breast cancer (BC) in general, how they influence different BC subtypes has remained poorly studied. Here, we investigated the prognostic value of M2-like TAMs (CD163+) that mediate several pro-tumoral functions, and all TAMs (CD68+) in a patient cohort of 278 non-metastatic BC cases, half of which were HER2+. Our results indicate that M2-like TAMs were associated with a poor outcome in HER2+ BC, in which a high CD163+ TAM count was independently associated with an inferior outcome regardless of hormone receptor status and the use of adjuvant trastuzumab. In summary, our results suggest that the prognostic value of M2-like TAMs is especially significant in HER2+ BC; these patients might benefit from combination treatments that include therapies targeting macrophage function. Tumor-associated macrophages (TAMs) are associated with a poor outcome in breast cancer (BC), but their prognostic value in different BC subtypes has remained somewhat unclear. Here, we investigated the prognostic value of M2-like TAMs (CD163+) and all TAMs (CD68+) in a patient cohort of 278 non-metastatic BC patients, half of whom were HER2+ (n = 139). The survival endpoints investigated were overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS). In the whole patient cohort (n = 278), a high CD163+ TAM count and a high CD68+ TAM count were associated with a worse outcome (p ≤ 0.023). In HER2+ BC, a high CD163+ TAM count was an independent factor for a poor prognosis across all the investigated survival endpoints (p < 0.001). The prognostic effect was evident in both the HER2+/hormone receptor-positive (p < 0.001) and HER2+/hormone receptor-negative (p ≤ 0.012) subgroups and regardless of the provision of adjuvant trastuzumab (p ≤ 0.002). In HER2-negative BC, the CD163+ TAM count was not significantly associated with survival. These results suggest that a high CD163+ TAM count predicts an inferior outcome, especially in HER2+ BC patients, and as adjuvant trastuzumab did not overcome the poor prognostic effect, combination treatments including therapies targeting the macrophage function could represent an effective therapeutic approach in HER2+ BC. [ABSTRACT FROM AUTHOR]