Abstract Purpose To compare the complication rates of lower extremity (LE) and upper extremity (UE) peripherally inserted central catheters (PICCs) in neonates with gastroschisis. Methods In this retrospective comparative study, neonates with gastroschisis admitted to a level IIId NICU between 2004 and 2013 were identified. Catheter dwell time and complication rates (infiltration, phlebitis, occlusion, migration, infection and thrombosis) between the initial UE and LE PICCs were compared. Results Forty (31%) and eighty-nine (69%) neonates with gastroschisis had their initial PICCs placed from their LE and UE, respectively. Complication rates were significantly higher when PICCs were inserted from LE, especially during silo-reduction and within 5days after abdominal closure (LE: 20% vs. UE: 3.4%, p<0.01). LE PICCs were 5.0 times more likely to have complications than UE PICCs (OR 95% CI: 1.2–21.5) during this time period. In particular LE PICCs had significantly higher rates of infiltration (LE: 11.5% vs. UE: 1.4%; p=0.025) and phlebitis (LE: 11.5% vs. UE: 0%; p<0.01) in patients who underwent silo-reduction. Conclusion LE PICCs are associated with significantly increased risks of infiltration and phlebitis in neonates with gastroschisis during silo-reduction and within 5days after abdominal closure.