To investigate the predictive and concurrent validity of magnetic resonance imaging (MRI)-based cartilage thickness change between baseline (BL) and year-two (Y2) follow-up (predictive validity) and between Y2 and Y4 follow-up (concurrent validity) for symptomatic and radiographic knee osteoarthritis (OA) progression during Y2→Y4. 777 knees from 777 Osteoarthritis Initiative (OAI) participants (age: 61.3 ± 9.0 years, BMI: 30.1 ± 4.8 kg/m2) with Kellgren Lawrence (KL) grade 1–3 at Y2 (visit before progression interval) had cartilage thickness measurements from 3T MRI at BL, Y2 (n = 777), and Y4 (n = 708). Analysis of covariance and logistic regression were used to assess the association of pain progression (≥9 WOMAC units scale 0–100, n = 205/572 with/without progression) and radiographic progression (≥0.7 mm minimum joint space width (mJSW) loss, n = 166/611 with/without progression) between Y2 and Y4 with preceding (BL→Y2) and concurrent (Y2→Y4) change in central medial femorotibial (cMFTC) compartment cartilage thickness. Symptomatic progression was associated with concurrent (Y2→Y4: −305 ± 470 μm vs −155 ± 346 μm, Odds ratios (OR) = 1.5 1.2, 1.7) but not with preceding cartilage thickness loss in cMFTC (−150 ± 276 μm vs −151 ± 299 μm, OR = 0.9 95% CI: 0.8, 1.1). Radiographic progression, in contrast, was significantly associated with both concurrent (−542 ± 550 μm vs −98 ± 255 μm, OR = 3.4 2.6, 4.3) and preceding cMFTC thickness loss (−229 ± 355 μm vs −130 ± 270 μm, OR = 1.3 1.1, 1.5). These results extend previous reports that did not discern predictive vs concurrent associations of cartilage thickness loss with OA progression. The observed predictive and concurrent validity of cartilage thickness loss for radiographic progression and observed concurrent validity for symptomatic progression provide an important step in qualifying cartilage thickness loss as a biomarker of knee OA progression. NCT00080171.