In several malignant tumors including lymphoma, macrophages that infiltrate tumor tissues are called tumor-associated macrophages (TAMs). We discovered that TAMs, especially the CD163+ alternatively activated phenotype (M2), were closely involved with progression of adult T-cell leukemia/lymphoma (ATLL). We used CD68 (a pan-macrophage marker) and CD163 (an M2 marker) to immunostain 58 ATLL samples. Statistical analyses showed that a high number of CD68+ TAMs and an increased percentage of CD163+ cells among the TAMs were associated with a worse clinical prognosis; multivariate analysis indicated that the percentage of CD163+ cells was an independent prognostic factor. We also carried out in vitro coculture experiments with ATLL cell lines (ATN-1 and TL-Mor) and monocyte-derived macrophages and found that direct coculture with M2 macrophages significantly increased BrdU incorporation into ATLL cell lines. A cytokine array analysis showed that macrophage-derived soluble factors including C5a, tumor necrosis factor-α, growth-related oncogene-α, CCL1/I-309, and interleukin-6 stimulated ATLL cell lines. CD163 expression in macrophages was strongly induced by direct contact with ATN-1 cells, and downregulation of CD163 in macrophages significantly suppressed growth of cocultured ATN-1 cells. These results suggest that interaction between M2 macrophages and lymphoma cells may be an appropriate target in treatment of patients with ATLL.