Enlargement of the left ventricle (LV) is an important marker of adverse cardiac remodeling and poor prognosis. Previous studies demonstrated increased cardiovascular risk in small subsets of patients with a small LV chamber size; however, the prognostic implications of small chamber size in the general population remains unclear. This study aimed to examine the prognosis of a small LV chamber in a large general cohort. All consecutive subjects who underwent echocardiography examinations from 2011 to 2023 were retrieved for analysis. Small chamber size was defined as end-diastolic diameter <42 mm for men and 37.8 mm for women as per American Society of Echocardiography guidelines. The primary end point for the study was all-cause mortality. A total of 46,529 subjects (mean age 60 ± 19 years, 56% men) were included, of whom 3,787 had a small LV chamber size. Clinical variables associated with small chamber included increasing age and lower body surface area. Echocardiographic variables included higher relative wall thickness and E/e' ratio. On the multivariable analysis, the presence of a small LV was significantly associated with mortality (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.22 to 1.46, p <0.001). This finding was significant in older (over 65 years) (HR 1.30, 95% CI 1.19 to 1.41, p <0.001) and younger (HR 2.09, 95% CI 1.81 to 2.41, p <0.001) subjects and in men and women. In conclusion, in this retrospective large cohort study, small LV chamber size was significantly associated with mortality in a broad range of patients. Further study is necessary to elucidate mechanisms and design preventive strategies.