Alterations in the serotonin (5-HT) system have been related to impulsive aggression and suicidal behavior, common features of the borderline personality disorder (BPD). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis. Two isoforms are known, TPH-1 and TPH-2. TPH-1 has been correlated to various psychiatric and behavioral disorders by gene polymorphism association studies. We aimed to determine whether specific TPH-1 haplotypes associate with BPD. A case-control design was employed. The control group included 98 women without psychiatric history. In all, 95 patients were included, all Caucasian women with a BPD diagnosis who had attempted suicide at least twice during their lifetime. Exclusion criteria were: (i) substance dependence; (ii) dementia or other irreversible organic brain syndromes; (iii) psychotic disorders or major depressive illness with melancholic features; (iv) life-threatening eating disorders. Six single-nucleotide polymorphisms (SNPs) were found at significant linkage disequilibrium across 23 kb of the TPH-1 gene in both patients and controls, suggesting a haplotype block structure. While no individual SNP showed association, several haplotypes associated with the BPD group. In particular, one six-SNP haplotype was absent from the control group while representing about one-quarter of all haplotypes in the BPD group (corrected P<<10(-5)). A 'sliding window' analysis attributed the strongest disease association to haplotype configurations located between the gene promoter and intron 3. We conclude that TPH-1 associates with BPD in suicidal women. Our data support the expectation that haplotype analysis is superior to single locus analysis in gene-disease, case-control association studies.