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Abstract Introduction The experiment was undertaken to estimate the effect of BMSC seeding in different scaffold incorporation with HBO on the repair of a seawater-immersed bone defect. And future compared n-HA/PLGA with β-TCP/PLGA as a scaffold in treatment effect of the seawater-immersed bone defect. Methods Sixty New Zealand White rabbits with standard seawater defect in radius were randomly divided into group A (implant with nothing), group B (implanted with autogenous bone), group C (implanted with n-HA/PLGA/BMSCs), and group D (implanted with β-TCP/PLGA/BMSCs). After the implant, each rabbit receives HBO treatment at 2.4 ATA 100% oxygen for 120 min/day for 2 weeks. Radiograph, histological, and biomechanical examinations were used to analyze osteogenesis. Result X-ray analysis shows that n-HA/PLGA/BMSCs and β-TCP/PLGA/BMSCs could accelerate the new bone formation, and the new bone formation in group C was larger than that in group D or group A and close to group B (P < 0.05). After 12 weeks, in group A, the defect without scaffold shows a loose connect tissue filled in the areas. The medullary canal in group B was recanalized. Defects in groups C and D show a larger number of woven bone formation. The new woven bone formation in defect areas in group C was larger than that in group D. The mechanical examination revealed ultimate strength at 12 weeks was group D > group C > group B > group A (P < 0.05). Conclusion Scaffolds of n-HA/PLGA and β-TCP/PLGA incorporation with HBO and BMSCs were effective to treat seawater-immersed bone defect, and n-HA/PLGA was more excellent than β-TCP/PLGA.