Purpose: The objective of this study was to evaluate peri-implant bone formation and osseointegration at titanium implants coated with multiple layers of recombinant human bone morphogenetic protein-2 (rhBMP-2) cDNA placed into canine mandibles. Materials and Methods: The rhBMP-2 plasmid was assembled on sandblasted/dual-acid-etched pure titanium implant surfaces using layer-by-layer assembly. The rhBMP-2 plasmid-coated implants were placed into the edentulous posterior mandibles of 12 adult beagle dogs. Implants without the rhBMP-2 plasmid coating served as controls. Treatments were randomized between jaw quadrants, and four implants were placed in each mandibular quadrant. After 4, 8, and 12 weeks in situ, mandibles were retrieved and prepared for removal torque testing and histomorphometric evaluation. Results: Eight layers of rhBMP-2 plasmid were assembled onto the implant surfaces. Histomorphometric analysis showed that, after 4 and 8 weeks of healing, the intrathread bone area (BA) was slightly higher for test implants (54.21% and 59.56%) than for control implants (38.48% and 54.98%), respectively, but no statistically significant differences were seen at any time points. Mechanical tests showed that the mean removal torque values of the rhBMP-2 cDNA-coated implants were greater than those of the control implants after 8 weeks of healing (91 Ncm versus 61 Ncm; P = .31). Conclusion: Coating implants with multiple layers of an rhBMP-2 plasmid did not promote peri-implant bone formation and osseointegration in this model.