Twelve patients with stable congestive heart failure and left ventricular dysfunction were enrolled in a double-blind, randomized crossover trial of famotidine, cimetidine and placebo to determine whether histamine type 2 (H2) antagonists adversely affect left ventricular systolic performance. Two-dimensional echocardiograms were obtained at baseline, after 4 days of oral treatment with standard doses of famotidine and cimetidine, and placebo, and at the conclusion of the trial. The baseline mean ejection fraction was 19 +/- 7%. The changes in ejection fraction were +2 +/- 11% (95% confidence interval [CI] -5 to 9%) with famotidine, +3 +/- 10% (95% CI -3 to 10%) with cimetidine, and -3 +/- 7% (95% CI -8 to 2%) with placebo. There were no significant differences in changes in ejection fraction among the 3 experimental treatments (p = 0.22; analysis of variance). The changes in end-systolic wall stress/volume ratios from baseline were +6 +/- 21% (95% CI -6 to 18%) for famotidine, +8 +/- 29% (95% CI -8 to 25%) for cimetidine, and +2% +/- 29% (95% CI -15 to 18%) for placebo (p = 0.69; analysis of variance). No patient had a worsening of symptoms during therapy. Despite previous reports that H2 antagonists may depress left ventricular systolic function, at standard doses these agents result in no decrease in left ventricular systolic function in patients with chronic congestive heart failure.