The in vivo precision (reproducibility) of quantitative MRI is of particular importance in osteoarthritis (OA) progression of small magnitude and response to therapy. In this study, three-dimensional high-resolution MRI performed at 7 T was used to assess the short-term reproducibility of measurements of mean tibial cartilage thickness in a meniscectomized guinea pig model of OA. MR image acquisition was repeated five times in nine controls (SHAM) and 10 osteoarthritic animals 3 months after meniscectomy (MNX), in vivo. The animals were then killed for histomorphometric assessment and correlation with the MRI-based measurements. Medial tibial cartilage thickness was measured on MR images using semi-automatic dedicated 3D software developed in-house. The reproducibility of measurements of cartilage thickness was assessed by five repeated MRI examinations with a short recovery delay between examinations (48 h). The computed coefficients of variation were 8.9% for the SHAM group and 8.2% for the MNX group. The coefficients of variation were compatible with expected thickness variations between normal and pathological animals. A positive agreement and significant partial correlation (Spearman r' = 0.74; P < 0.01) between the MRI and histomorphometric data was established. Three-dimensional high-resolution MRI is a promising non-invasive research tool for in vivo follow-up. This modality could be used for staging and monitoring therapy response in small-animal models of OA.