Bone mass is partly genetically determined. The genes involved are, however, still largely unknown. Transforming growth factor-beta 1 (TGF-beta 1) is considered a putative regulator of osteoclastic-osteoblastic interaction (coupling). The aim of the present study was therefore to examine whether possible variants of the TGF-beta 1 gene are related to bone mass and osteoporosis. We examined 161 osteoporotic women (at least one low energy spinal fracture) and 131 normal women. We investigated sequence variations in the TGF-beta 1 gene using the single-stranded conformation polymorphism (SSCP) technique combined with DNA sequencing. Seven patients were heterozygous for a cytosine to thymidine base substitution at position 76 in exon 5 (C788-T) (corresponding to position 788 in the TGF-beta 1 cDNA), resulting in a threonine to isoleucine amino acid shift at position 263 in the TGF-beta 1 propeptide (Thr263-Ile). Ten other patients had a one base deletion in the intron sequence 8 bases prior to exon 5 (713-8delC), which could influence splicing. Five normal women exhibited the C788-T sequence variant, and two the 713-8delC. The prevalence of 713-8delC was significantly higher in the osteoporotic group (chi 2 = 4.02, p < 0.05). Osteoporotic patients with the 713-8delC variant had increased levels of bone alkaline phosphatase (p < 0.05). If the osteoporotic patients with a z score of the lumbar spine below -1 were examined separately, we found increased serum levels of bone alkaline phosphatase (p < 0.05), increased urinary excretion of hydroxyproline (p < 0.05), and reduced bone mass of the lumbar spine (p < 0.05) in patients with 713-8delC. No correlation to bone mass was demonstrated in the normal women, but 713-8delC was associated with increased serum levels of bone alkaline phosphatase (p < 0.05). The sequence variation, 713-8delC, in the TGF-beta 1 gene is more frequent in patients with osteoporosis compared to normal controls. The 713-8delC variant seems to be associated with very low bone mass in osteoporotic women with low bone mass and increased bone turnover in both osteoporotic and normal women.