The hybrid approach to palliation of hypoplastic left heart syndrome using pulmonary artery bands, a patent ductus arteriosus (PDA) stent, and atrial septostomy has been well described. One potential complication of hybrid stage 1 palliation is the development of neointimal formation and in-stent stenosis (ISS). This study aimed to identify predictors of ISS development. Patients who underwent hybrid stage 1 palliation between 2002 and 2010 were included in the study. The clinical information included oxygen saturation, weight, vital signs, and medications. Echocardiographic data included ventricular function, degree of tricuspid regurgitation, and velocity through the PDA stent and pulmonary artery bands. Hemodynamic data from interstage catheterizations were similarly noted. Patients who developed clinically significant ISS requiring either transcatheter intervention or early stage 2 repair were compared with those who did not. Of the 66 patients included in the study, 40 were boys (61 %). The median age at hybrid palliation was 7 days (range, 1-93 days), and the median initial weight was 3.2 kg (range, 1.4-5 kg). In 13 patients (20 %), ISS developed. The mean initial weight was significantly greater in the ISS group (3.5 ± 0.5 vs. 3.0 ± 0.6 kg) (p = 0.03). The mean oxygen saturations did not differ significantly between the no-ISS group (82.2 % ± 5.7 %) and the ISS group (81.4 % ± 2.0 %) (p = 0.31). The mean PDA velocities were higher in the ISS group (2.7 ± 0.4 m/s) and increased at a faster rate than in the no-ISS group at (2.4 ± 0.4 m/s) (p = 0.01). The degree of tricuspid regurgitation, ventricular function, and pulmonary artery band gradients shown by echocardiography were similar in the two groups. The development of ISS after hybrid stage 1 palliation can lead to interstage interventions or earlier comprehensive stage 2 repair. Patients with greater initial weight and a lower stent-to-weight ratio are more likely to develop ISS. The cause of ISS is complex, and additional investigation of its etiology currently is ongoing.