The prognostic significance of tumor-associated macrophages (TAMs) in multiple myeloma (MM) in the era of novel drugs remains unclear. CD163 expression was detected by immunohistochemistry to determine the number of TAMs in 198 MM patients receiving bortezomib-based regimens and the data were used to evaluate its relevance with clinical characteristics, treatment response, and prognosis. Patients with high levels of infiltrated CD163+ TAMs (>55/HPF) at diagnosis tended to have more adverse clinical characteristics. Patients with high CD163+ TAM content (>55/HPF) at diagnosis had worse progression-free survival (PFS) (P<0.001) and overall survival (OS) (P<0.001),and achieved lower complete remission (CR)/near-CR rate (P<0.001), than patients with low CD163+ TAM levels. Multivariate analysis revealed that CD163+ TAM content was an independent adverse prognostic factor for PFS and OS. Our data indicated that CD163+ TAM content at diagnosis is a powerful predictor of prognosis for MM in the era of novel drugs, and this discovery offers new insight into potential therapeutic strategies.