AbstractThis preliminary study quantified tibia cartilage thickness (Cart.Th), subchondral bone plate thickness (SBPl.Th) and subchondral trabecular bone (STB) microarchitecture in subjects with varus‐ or valgus‐ malaligned knees diagnosed with end‐stage knee osteoarthritis (OA) and compared them to controls (non‐OA). Tibial plateaus from 25 subjects with knee‐OA (undergoing knee arthroplasty) and 15 cadavers (controls) were micro‐CT scanned (17 µm/voxel). Joint alignment was classified radiographically for OA subjects (varus‐aligned n = 18, valgus‐aligned n = 7). Cart.Th, SBPl.Th, STB bone volume fraction (BV/TV) and their medial‐to‐lateral ratios were analyzed in anteromedial, anterolateral, posteromedial and posterolateral subregions. Varus‐OA and valgus‐OA were compared to controls. Compared to controls (1.19–1.54 mm), Cart.Th in varus‐OA was significantly lower anteromedially (0.58 mm, −59%) and higher laterally (2.19–2.47 mm, +60–63%); in valgus‐OA, Cart.Th was significantly higher posteromedially (1.86 mm, +56%). Control medial‐to‐lateral Cart.Th ratios were around unity (0.8–1.1), in varus‐OA significantly below (0.2–0.6) and in valgus‐OA slightly above (1.0–1.3) controls. SBPl.Th and BV/TV were significantly higher medially in varus‐OA (0.58‐0.72 mm and 37–44%, respectively) and laterally in valgus‐OA (0.60–0.61 mm and 32–37%), compared to controls (0.26–0.47 mm and 18–37%). In varus‐OA, the medial‐to‐lateral SBPl.Th and BV/TV ratios were above unity (1.4–2.4) and controls (0.8–2.1); in valgus‐OA they were closer to unity (0.8‐1.1) and below controls. Varus‐ and valgus‐OA tibia differ significantly from controls in Cart.Th, SBPl.Th and STB microarchitecture depending on joint alignment, suggesting structural changes in OA may reflect differences in medial‐to‐lateral load distribution upon the tibial plateau. Here we identified an inverse relationship between cartilage thickness and underlying subchondral bone, suggesting a whole‐joint response in OA to daily stimuli.