BACKGROUND: Patients undergoing hip fracture surgery often experience acute post-operative cognitive dysfunction (APOCD). The pathogenesis of APOCD is probably multifactorial, and no single intervention has been successful in its prevention. No studies have investigated the incidence of APOCD after hip fracture surgery in an optimized, multimodal, peri-operative rehabilitation regimen. METHODS: One hundred unselected hip fracture patients treated in a well-defined, optimized, multimodal, peri-operative rehabilitation regimen were included. Patients were tested upon admission and on the second, fourth and seventh post-operative days with the Mini Mental State Examination (MMSE) score. RESULTS: Thirty-two per cent of patients developed a significant post-operative cognitive decline, which was associated with several pre-fracture patient characteristics, including age and cognitive function, but also the number of peri-operative transfusions. The development of APOCD was also associated with impaired post-operative rehabilitation and an increased length of stay. APOCD was associated with the development of a major medical complication in 35% of all patients. In 65% of patients developing APOCD without a concomitant medical complication, the only risk factors were cognitive level and regular anti-psychotic treatment. CONCLUSION: On the basis of current evidence, APOCD is prevalent amongst hip fracture patients despite multimodal intervention; future research should therefore focus on defining subgroups of hip fracture patients amenable to specific prophylactic or interventional measures against APOCD.