This study tested for longitudinal changes in femoral cartilage T2 relaxation time and thickness in fast-progressing medial femorotibial osteoarthritis (OA). From the Osteoarthritis Initiative (OAI) database, nineteen knees fulfilled the inclusion criteria, which included medial femorotibial OA and sequential progression from Kellgren-Lawrence grade (KL) 1 to KL2 to KL3 within five years. Median T2 value and mean thickness were calculated for six condylar volumes of interest (VOIs; medial/lateral anterior, central, posterior) and six sub-VOIs (medial/lateral anterior external, central, internal). T2 value and thickness changes between severity timepoints were tested using repeated statistics. T2 values increased between KL1 and KL2 and between KL1 and KL3 in the medial compartment (p ≤ 0.02), whereas both increases and decreases were observed between the same timepoints in the lateral compartment (p ≤ 0.02). Cartilage thickness decreased in VOI/subVOIs of the medial compartment from KL1 to KL2 and KL3 (p ≤ 0.014). Cartilage T2 value and thickness changes varied spatially over the femoral condyles. While all T2 changes occurred in the early radiographic stages of OA, thickness changes occurred primarily in the later stages. These data therefore support the use of T2 relaxation time analyses in methods of detecting disease-related change during early OA, a valuable period for therapeutic interventions.