Background: The short form of the indel promoter polymorphism (5HTTLPR) of the serotonin transporter gene (SLC6A4) and a history of child abuse have been reported to be associated with an increased risk for the development of depression. A child abuse history has also been associated with more rapid heart rate reactions. Methods: A retrospective chart review identified 282 patients with major depression who had been hospitalized and genotyped for the 5HTTLPR polymorphism. A subgroup of 185 females of European ancestry was also identified and analyzed. While hospitalized, heart rate was measured. Child abuse history was documented during the diagnostic evaluation. Analyses of the relationship between 5HTTLPR genotype, history of child abuse, and admission heart rate were conducted. Results: No main effect on heart rate from the 5HTTLPR genotype or a child abuse history was demonstrated for the entire sample or the subgroup of female patients. However, a genotype-by-abuse interaction was associated with resting heart rate on admission to the hospital (P<.05). Depressed patients, who were homozygous for the long allele and who had been abused, had a heart rate on hospital admission, which was statistically higher than patients with the same genotype but who had not been abused. These findings were consistent both for the 282 patients (7.2 bpm higher) as well as for the subgroup of 185 female patients of European ancestry (9.6 bpm higher). Conclusions: A 5HTTLPR genotype interaction of elevated heart rate with a history of child abuse was demonstrated in depressed psychiatric inpatients. Depression and Anxiety 28:227-233, 2011. © 2010 Wiley-Liss, Inc.