INTRODUCTION: Cartilage thickness and volume loss measurements using quantitative magnetic resonance imaging (qMRI) are suggested to detect significant cartilage changes over short time intervals. We aimed to compare these two different approaches looking at the global knee and subregions, using data from an osteoarthritis (OA) multicentre randomised clinical trial. METHODS: Three hundred and fifty-five patients with symptomatic knee OA were recruited for a two-year, double-blind, randomised clinical trial evaluating the effect of 200 mg licofelone twice daily and 500 mg naproxen twice daily on cartilage loss, and 301 patients had baseline MRI. MRIs were performed at baseline, 6, 12 and 24 months. Cartilage volume and thickness in the global joint, medial and lateral compartments, and central weight-bearing subregions of the medial and lateral femoral condyles and tibial plateaus were analysed. Data were analysed for the mean value imputed for intent-to-treat (ITT-MVI) and statistical analyses were performed using two-sample Student's t-test. RESULTS: Cartilage mean thickness loss in the global joint, lateral and medial compartments, as well as in medial compartments stratified according to patients with or without meniscal extrusion, was significantly less in the licofelone compared with the naproxen group at 12 and 24 months. Interestingly, these data were similar to those found when using cartilage volume loss as an outcome. Although greater cartilage volume and mean thickness loss was seen in central weight-bearing subregions of the medial and lateral compartments compared with the whole compartment and also in patients with meniscal lesions/extrusion, suggesting good sensitivity to change, its high standard deviation precluded for the condyles a high statistical power and abrogated statistically significant differences between the treatment groups. CONCLUSIONS: These data demonstrate that both the measurement of cartilage thickness and that of cartilage volume provide the same level of sensitivity to estimate cartilage loss in a clinical trial. However, the potential of gaining statistical power with the use of thickness/volume change in knee subregions as an outcome seems negated by high inter-patient variability. Moreover, there is no superiority in statistical power by selecting patients with meniscal extrusion.