The objective of this study was to analyze the responses of bone‐forming osteoblasts to Ti‐6Al‐4V implant material coated with silica‐calcium phosphate nanocomposite (SCPC50). Osteoblast differentiation at the interface with SCPC50‐coated Ti‐6Al‐4V was correlated to the adsorption of high amount of serum proteins, high surface affinity to fibronectin, Ca uptake from and P and Si release into the medium. SCPC50‐coated Ti‐6Al‐4V adsorbed significantly more serum protein (p < 0.05) than control uncoated substrates. Moreover, Western blot analysis showed that the SCPC50 coating had a high affinity for serum fibronectin. Protein conformation analyses by FTIR showed that the ratio of the area under the peak for amide I/amide II bands was significantly higher (p < 0.05) on the surface of SCPC50‐coated substrates than that on the surface of the control uncoated substrates. Moreover, ICP − OES analyses indicated that SCPC50‐coated substrates withdrew Ca ions from, and released P and Si ions into, the tissue culture medium, respectively. In conjunction with the favorable protein adsorption and modifications in medium composition, MC3T3‐E1 osteoblast‐like cells attached to SCPC50‐coated substrates expressed 10‐fold higher level of mRNA encoding osteocalcin and had significantly higher production of osteopontin and osteocalcin proteins than cells attached to the uncoated Ti‐6A1‐4V substrates. In addition, osteoblast‐like cells attached to the SCPC50‐coated substrates produced significantly lower levels of the inflammatory and osteoclastogenic cytokines, IL‐6, IL‐12p40, and RANKL than those attached to uncoated Ti‐6Al‐4V substrates. These results suggest that SCPC50 coating could enhance bone integration with orthopedic and maxillofacial implants while minimizing the induction of inflammatory bone cell responses. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2012.