Osseointegrated implants are a common therapy for the elderly population as lifespan increases. Understanding the effects of age and sex on osseointegration is important for successful implant therapy. Therefore, the response of primary human osteoblasts (HOB) to implant materials was studied. HOBs were obtained by outgrowth of cells from bone from orthopaedic procedures and categorized as Young (Y), <15; Middle (M), 30-50; and Old (O), >60 years old. Initially the HOB phenotype was determined on tissue culture plastic. Alkaline phosphatase (ALP) staining and activity were significantly increased in HOBs from older patients. Message levels of type I collagen (COL), bone sialoprotein (BSP) and ALP were significantly higher (from 2.3- to 3.8-fold) in Y subjects compared to M and O patients at 2 weeks. Studies of the response of HOBs to implant materials were undertaken using Ti-6Al-4V disks prepared in a manner similar to orthopaedic implants. A 1.4-fold (p<0.05) increase in cell attachment was found in HOBs from Y compared with O in female subjects but not in male subjects. Cell proliferation at 24 h was not significantly different by age or sex, nor was DNA content different at 2 and 4 weeks. Mineralization in HOB-implant cultures was 2.3-fold higher in Y than in O, and 1.7-fold higher in Y compared to M HOBs from female but not male subjects at 4 weeks. Northern blot and RT-PCR analysis at 2 weeks of culture showed significantly higher levels (1.6-2.3-fold) of COL, BSP, and osteocalcin (OC) mRNAs in Y HOBs compared to M and O HOBs from female subjects. We conclude that human osteoblasts from older female patients have a decreased ability to form bone on implants.