The osteoclast is a hematopoietic cell derived from CFU-GM and branches from the monocyte-macrophage lineage during the differentiation process. Biological environment appears to be crucial for osteoclast formation and activity. It has been reported that bone remodeling following implant placement requires a coordinated activity by osteoclasts and osteoblasts. The response of such cells at the bone-implant interface has been suggested to be affected by the structural and morphological features of the biomaterial surface. To shed more light on this topic we performed a multiparametric analysis of murine monocytes response to different titanium surfaces. These cells, RAW 264.7 type TIB-71, represent a very useful system because they differentiate into osteoclasts following treatment of definite doses of the osteoclast-differentiation factor RANKL and macrophage colony-stimulating factor (M-CSF). Cells, cultured on glass (control), on grade 3 machined and on titanium pull-spray superficial-TPSS surfaces disclosed profound different responses in terms of morphological rearrangements, adhesion, and differentiation abilities. Indeed, after 14 days, cells cultured on glass and machined surfaces were uniformly distributed, while, on the TPSS surface cells strictly aggregated into small isolated clusters were observed. In addition, cells cultured on the machined surface displayed a higher adhesion ability, while cells cultured on the rougher surface disclosed a more evident capability to differentiate. These results could explain the higher bone-implant contact percentage found around implants with rougher surfaces and suggest that osteoclasts may play an important role in the initial period after implant placement to prime or prepare the implant surface for the osteoblast activity.