Background: While propranolol hydrochloride (PH) is being more widely used in adult patients, its administration in the neonatal period as well is progressively on the rise in our time. With the increasing use of PH in the neonatal age period, worries resulting from the potential adverse effects of the agent on vital organs, such as brain, in particular, have come to the fore. Such concerns increase even more when PH is used in treating preterm infants. Our study, aiming to clarify these increasing concerns, is the first clinical one of its kind in the literature, conducted on very preterm infants, the patient group most vulnerable to PH treatment. Aims: To investigate possible short- and long-term side effects of using PH during the neonatal period and to provide information to clinicians regarding such side effects. Study Design: Case-control study. Materials and Methods: This was a double-blind, randomized, and placebo-controlled trial. In the study, we included 36 very preterm infants subjected to PH treatment (0.5 mg/kg/6 h) initiated in the first postnatal month and lasting for approximately 1 month (PH group [PHG]) and 40 very preterm infants who received distilled water in place of PH (control group [CG]). The gestational age of all infants in the study was below 31+6 weeks, and their birth weight was under 1500 g. The patients' vital functions and physical development were monitored and recorded in patient follow-up forms. At approximately 1 year of age (CG: 9.73 +/- 4.56 months and PHG: 10.8 +/- 5.73 months), the Ankara Developmental Screening Inventory (ADSI) and the Denver Developmental Screening Test II (DDST-II) were used to assess the mental development of the children. Results: In the PHG patients, PH treatment was initiated at 27.0 +/- 2.7 days of life and lasted for 26.5 +/- 8.7 days. The newborns in the CG received distilled water for similar durations. A statistically significant difference in blood sugar levels was detected between CG (78.4 +/- 12.5) and PHG (65.6 +/- 7.5) (P = 0.006). However, no statistically significant difference was found between the two groups in terms of physical and mental development (ADSI and DDST-II) of the children at the end of the study (P > 0.05). Conclusions: When used on very preterm infants, PH may have some temporary effects on the patients' vital functions in the short term; however, no serious side effects were detected that may affect the physical and mental development in the long run.