Introduction: Oral bisphosphonates are first-line agents for treating osteoporosis in men, but there are no studies regarding efficacy of oral bisphosphonates for treatment of osteoporosis in ambulatory male adults with intellectual disability. Methods: Nine adult males with intellectual disability and increased fracture risk had been treated with weekly or monthly oral bisphosphonates, vitamin D and calcium for 1-3 years. Post-treatment bone mineral density (BMD), serum 25(OH)D, parathyroid hormone and C-telopeptide of type I collagen were then determined for the first time. Results: Weekly or monthly oral bisphosphonates were well tolerated and led to significant increases in BMD in all 9 individuals. Serum 25(OH)D level enhanced the "percent increase of BMD" that occurred in response to bisphosphonate treatment (p < 0.05). Conclusions: Weekly or monthly oral bisphosphonates are well tolerated by ambulatory adult males with ID and are effective in increasing BMD. Higher serum levels of vitamin D appear to improve the efficacy of bisphosphonates and therefore reduce fracture risk in adult males with intellectual disability.