OBJECTIVE: Female C57BL6 mice exhibit less severe chondropathy compared with male mice. We tests the robustness of this observation and explore underlying mechanisms. METHODS: OA was induced in male and female C57BL6 or DBA1 mice (n=6-12 per group) using destabilisation of the medial meniscus (DMM), or partial meniscectomy (PMX). Some mice were ovariectomised (OVX) (n=30). In vivo repair was assessed by focal cartilage defect or by joint immobilisation (sciatic neurectomy) after DMM. Histology, gene expression of whole knees, behavioural analysis using Laboratory Animal Behavior Observation Registration and Analysis System (LABORAS), and by Linton incapacitance, were used (n=7-10/group). RESULTS: Female mice displayed less severe chondropathy (20-75% reduction) across both strains, and after both surgeries. Male and femal activity levels after PMX were similar. Some repair-associated genes were increased in female joints after surgery but in vivo, no repair differences were evident. Despite reduced chondropathy, females developed pain-like behaviour at the same time as males. At established pain-like behaviour (10 weeks post PMX), females significantly upregulated pain-associated genes including glial cell derived neurotrophic factor (2.54±0.30 fold), neurturin (6.71±1.24), and neurotrophic factors 3 (1.92±0.27) and 5 (2.89±0.48). Inflammatory genes were not regulated in painful joints in either sex. CONCLUSION: We confirm strong structural joint protection in female mice which is not due to activity or intrinsic repair differences. Female mice develop pain at the same time as males, but induce a distinct set of neurotrophins. We speculate that heightened pain sensitivity in females protects the joint by preventing overuse.