Objectives <p>This study evaluated immunohistochemical profiles associated with guided bone regeneration (GBR) using collagen membranes with different thickness-related mechanical properties to characterize membrane-related biological responses during lateral bone augmentation.</p> Methods <p>Standardized mandibular defects in beagle dogs were grafted with bone substitutes and covered with one of two collagen membranes with different thickness-related mechanical properties or left uncovered. At 8 and 16 weeks, tissues were analyzed for markers associated with osteogenesis (ALP), vascular/perivascular and myofibroblast-associated responses (α-SMA), inflammation-related cell profiles (iNOS and CD206), and bone remodeling (TRAP, Cathepsin K, and collagen type I).</p> Results <p>At 8 weeks, the FM group showed a trend toward higher numbers of CD206-positive cells in the coronal region. iNOS-positive cells did not differ significantly among groups in any region. However, most macrophage-related outcomes were not statistically significant. The SM group exhibited significantly greater collagen type I deposition, particularly in deeper regions, although this appeared to represent early unmineralized matrix rather than enhanced bone formation. TRAP-positive cells were more frequently observed in membrane-covered groups at both time points, mainly around biomaterials, suggesting remodeling-related activity. ALP, α-SMA, and Cathepsin K showed no significant intergroup differences. At 16 weeks, most immunohistochemical differences had diminished across all groups.</p> Conclusions <p>Collagen membranes with different thickness-related mechanical properties were associated with distinct early tissue responses during GBR healing. The FM group showed trends toward increased CD206-positive cells, whereas the SM group exhibited greater early collagen type I deposition. Because most inflammation-related outcomes were not statistically significant, these findings should be interpreted cautiously and considered exploratory.</p>