Interleukin-1alpha (IL-1alpha) stimulates bone resorption via osteoclasts. Mononuclear cells from patients with osteoporosis show increased IL-1alpha production, and IL-1alpha mRNA is more often detected in bone biopsies from osteoporotic compared to normal postmenopausal women. Polymorphisms have been identified in the IL-1alpha gene; however, none of these has been examined for an effect on bone phenotypes in Caucasians. We investigated if the polymorphisms in the IL-1alpha gene affect the risk of osteoporotic fractures, bone mineral density (BMD), and bone turnover in 462 osteoporotic patients and 336 normal controls. Based on previous studies of polymorphisms in the gene and data from the International Hap-Map Project, four polymorphisms needed examination in order to investigate the effect of known polymorphisms in the IL-1alpha gene. We examined C(-1202)-T(rs1800794), C(-889)-T(rs1800587), T(155 + 209)-C(rs2071373), C(155 + 320)-T(rs2856838), and G(398)-T(rs 17561) by Taqman and restriction fragment-length polymorphism assays. BMD was examined by dual-energy X-ray absorptiometry. Bone turnover was evaluated by serum osteocalcin, serum carboxy-terminal propeptide of human type I procollagen, serum bone-specific alkaline phosphatase, serum carboxy-terminal telopeptide of type I collagen, and urinary hydroxyproline/creatinine. Genotype distributions were in Hardy-Weinberg equilibrium. All polymorphisms were in strong linkage disequilibrium. The C allele of the C(155 + 320)-T polymorphism tended to be more common among patients with vertebral fractures (P = 0.06) and patients with BMD T score <-2.5 (P = 0.05). Furthermore, haplotype 1 was associated with reduced risk of having BMD T score <-2.5 (P = 0.02). None of the other polymorphisms or haplotypes was associated with fracture risk or BMD T score <-2.5. BMD and bone turnover were not associated with any of the genetic variants. In conclusion, all the polymorphisms within the IL-1alpha gene are in strong linkage disequilibrium and not convincingly associated with fracture risk, BMD, or bone turnover.