Prophylactic platelet transfusion has been adopted as a ubiquitous practice in management of thrombocytopenia in preterm infants to reduce the risk of bleeding. The objectives of this study were to report the prevalence of platelet transfusion among preterm infants with thrombocytopenia and to assess the association of platelet transfusion with mortality and morbidity in this population. A cross-sectional study that utilized National Inpatient Sample for the years 2000-2017 was conducted. All preterm infants delivered nationally with birth weight (BW) <1,500 g or gestational age <32 weeks were included. Analyses were repeated after stratifying the population into 2 BW subcategories <1,000 g and 1,000-1,499 g. Logistic regression analysis was performed to adjust for confounding variables. The study included 1,780,299 infants; of them, 22,609 (1.27%) were diagnosed with thrombocytopenia and 5,134 (22.7%) received platelet transfusion. Platelet transfusion was associated with significant increase in mortality (24.8 vs. 13.8%), retinopathy of prematurity (22.3 vs. 19.2%), severe intraventricular hemorrhage (18.3 vs. 10.1%), median length of hospital stays (51 vs. 47 days), and cost of hospitalization (USD 298,204 vs. USD 219,760). Increased mortality was noted in <1,000-g infants (aOR = 1.96, CI: 1.76-2.18, p < 0.001) and 1,000-1,499-g infants (aOR = 2.02, CI: 1.62-2.53, p < 0.001). Platelet transfusion increased over the years in infants with BW <1,000 g (p = 0.001) and in infants with BW 1,000-1,499 g (p < 0.001). Platelet transfusion is associated with increased mortality and comorbidities in premature infants. There is a trend for increased utilization of platelet transfusions over the study period.