This　study　explored　the　use　of　lithium　to　prevent　rat　steroid-related　osteonecrosis　of　the　femoral　head　(ONFH)　through　the　modulation　of　the　beta-catenin　pathway.　ONFH　was　induced　by　methylprednisolone　combined　with　lipopolysaccharide,　and　serum　lipids　were　analyzed.　ONFH　was　detected　by　hematoxylin-eosin　staining.　Micro-CT-based　angiography　and　bone　scanning　were　performed　to　analyze　vessels　and　bone　structure,　respectively.　Immunohistochemical　staining　for　peroxisome　proliferator-activated　receptor　gamma　(PPAR　gamma),　bone　morphogenetic　protein-2　(BMP-2),　and　vascular　endothelial　growth　factor　(VEGF)　was　analyzed.　Protein　levels　of　phospho-glycogen　synthase　kinase-3　beta　at　Tyr-216　(p-Tyr(216)　GSK-3　beta),　total　glycogen　synthase　kinase-3　beta　(GSK-3　beta)　and　beta-catenin,　as　well　as　mRNA　levels　of　GSK-3　beta　and　beta-catenin　in　femoral　heads,　were　assessed.　The　rate　of　empty　bone　lacunae　in　the　femoral　heads　was　lower　in　the　lithium　and　control　groups　than　in　the　model　group.　The　lithium　group　showed　preventive　effects　against　steroid-related　vessel　loss　by　micro-CT-based　angiography　and　VEGF　staining.　Lithium　treatment　improved　hyperlipidemia　and　reduced　PPAR　gamma　expression.　Moreover,　lithium　improved　steroid-related　bone　loss　in　micro-CT　bone　scans　and　BMP-2　staining　analyses.　Furthermore,　local　beta-catenin　was　reduced　in　steroid-related　ONFH,　and　lithium　treatment　increased　beta-catenin　expression　while　reducing　p-Tyr(216)　GSK-3　beta　levels.　The　local　beta-catenin　pathway　was　inhibited　during　steroid-related　ONFH.　Lithium　may　enhance　angiogenesis　and　stabilize　osteogenic/adipogenic　homeostasis　during　steroid-related　ONFH　in　rats　by　activating　the　beta-catenin　pathway.