Ultrasound enhancing agents (UEAs) are routinely used to improve transthoracic echocardiographic (TTE) image quality, yet anticipation of UEA need is a barrier to their use. Structured report data from 171,509 consecutive TTE studies in 97,515 patients who underwent TTE imaging from January 26, 2000, to September 20, 2018, were analyzed. Trends in UEA use and suboptimal image quality were examined. Among outpatients (92,291 TTE examinations, n=56,479), the data set was randomly split into a 75% derivation sample and a 25% validation sample. Logistic regression was used to model the composite of either UEA receipt or suboptimal image quality (two or more nonvisualized segments) using only variables available at the start of the TTE examination. Model performance was tested in the validation sample. A total of 4,444 TTE examinations (2.6%) in 3,827 patients (3.9%) involved UEAs, and 28,468 TTE examinations (16.6%) in 21,994 patients (22.5%) were suboptimal. UEA use increased over the observation period. Among TTE studies with suboptimal image quality, UEA use was lower in women (P<.0001). Among outpatients referred for TTE imaging, older age, greater weight, and higher heart rate best predicted UEA use or suboptimal image quality. Model performance in the validation sample was excellent (C statistic=0.74 [95% CI, 0.73-0.75]; calibration slope=1.11 [95% CI, 1.06-1.15]). In this large, single-center, retrospective study, UEA use remained substantially below rates of suboptimal image quality, despite increases over time. Among outpatients, a simple prediction rule using three routinely collected variables available before TTE image acquisition predicted potential benefit from UEAs with high accuracy. If confirmed in other cohorts, this rule may be used to identify patients who may benefit from intravenous placement for UEA administration before TTE image acquisition, thus potentially improving work-flow efficiency.