Background: Pulmonary hypertension is common in patients with heart failure (HF); however, for a given degree of left ventricular dysfunction, the range in pulmonary artery pressures (PAPs) is large. Polymorphisms of the serotonin transporter (5-HTT) gene have been implicated in contributing to smooth muscle dysfunction and remodeling of the pulmonary vasculature. This study examined the influence of a repeat length polymorphism in the promoter region of the 5-HTT gene on PAP between patients with HF and healthy control participants. Methods: A total of 90 patients with HF (age, 55 ± 14 years; left ventricular ejection fraction, 28% ± 10%; New York Heart Association, 2.0 ± 0.9) and 90 age- and sex-matched controls (CTL) (age, 51 ± 15 years; left ventricular ejection fraction, 63% ± 7%) were recruited. Patients with HF and CTL participants were divided into 3 genotype groups: homozygotes for the short variant (SS), homozygotes for the long variant (LL), and heterozygotes (LS). For both HF and CTL, there are 20 patients in the SS group, 41 in the LS, and 29 in the LL. Pulmonary artery pressure was calculated from the tricuspid regurgitant velocity. Results: Age and sex did not differ between the HF and CTL groups. Pulmonary artery pressure was higher in HF patients compared with CTL (38.9 ± 12.5 vs 27.7 ± 8.2 mm Hg, respectively; P < .01). There was a significant interaction between the HF and CTL groups for PAP by genotype (P < .03), with a significant genotype effect in HF (SS = 34.2 ± 8.6 vs LL = 43.2 ± 15.2 mm Hg; P < .05) but not in CTL. The HF group also demonstrated elevated left atrial diameter compared with CTL (48.0 ± 8.7 vs 32.8 ± 4.8 mm, respectively; P < .01), although no significant genotype difference was seen within either group. Conclusion: These results suggest that the LL variant of the 5-HTT is associated with elevated PAP in patients with HF.