In this matched cohort study using data from pediatric hospitals, we compared the incidence of hospital-acquired conditions (HACs) during clinical research hospitalizations to nonresearch hospitalizations. Using Pediatric Health Information System data for inpatient discharges January 2017-June 2022, we matched research hospitalizations (identified by International Classification of Diseases, Tenth Revision, diagnosis code) to nonresearch hospitalizations within hospital on age (±3 y), sex, discharge year (±2), and All Patients Refined Diagnosis Related Groups classification, severity of illness (±1), and risk of mortality (±1). We calculated the incidence (per 1000 discharges) and incidence rate (per 10,000 patient days) of HAC identified by International Classification of Diseases, Tenth Revision, codes and compare research versus nonresearch using logistic and Poisson regression, accounting for matching using generalized estimating equations and adjusting for sociodemographic factors and hospital utilization. We matched 7000 research hospitalizations to 26,447 nonresearch from 28 hospitals. Median age was 6.0 years (interquartile range, 10.6 y). Median length of stay was 4.0 days (interquartile range, 11.0 days) with longer stays among research hospitalizations ( P < 0.001). Incidence of HAC among research hospitalizations was 13.1 versus 7.2 per 1000 for nonresearch ( P < 0.001) and incidence rate 6.7 versus 4.5 per 10,000 patient days. Adjusting for sociodemographic and clinical factors, research stays had 1.65 times the odds of any HAC (95% confidence interval, 1.27-2.16; P < 0.001) and 1.38 times the incidence rate (95% confidence interval, 1.09-1.75; P = 0.009). Our findings indicate that pediatric research hospitalizations are more likely to experience HACs compared with nonresearch hospitalizations. These findings have important safety implications for pediatric inpatient clinical research that warrant further study.