To compare the rate and sensitivity to change of quantitative cartilage thickness change with magnetic resonance imaging (MRI) across specific radiographic strata of knee osteoarthritis (KOA) from central expert readings of the Osteoarthritis Initiative (OAI). Specifically, we explored whether Kellgren Lawrence grade (KLG) 2 knees with radiographic joint space narrowing (JSN) displayed greater cartilage loss than those without JSN, and whether knees with medial JSN grade2 had greater loss than those with grade1. One-year femorotibial cartilage thickness change was obtained for 836 knees, 112 without, and 724 with definite radiographic KOA based on baseline site readings. The maximum subregional cartilage loss, and cartilage thickness change in the total femorotibial joint (FTJ) and medial femorotibial compartment (MFTC) were analyzed across different radiographic strata (central vs site readings). The maximum subregional rate of change was significantly greater in central_KLG2 knees with than in those without JSN (172 ± 152 vs 134 ± 100 μm; P = 0.03). In contrast, the rate did not differ significantly between central_KLG1 knees with and without JSN. MFTC cartilage loss in central_medial_grade2 JSN knees was substantially and significantly greater than in grade1 knees (-70 ± 159 vs -31 ± 126 μm; P = 0.02). For comparison, the loss in grade3 knees was -72 ± 122 μm. In KLG2 knees, presence of radiographic JSN was associated with significantly and substantially greater rates of subregional cartilage loss. Differentiating knees with mild vs moderate medial JSN, and definite radiographic OA knees with vs without JSN is important in predicting structural progression of KOA, and for planning clinical trials testing the efficacy of disease modifying drugs (DMOADs).