To determine the incidence and risk factors of post-phototherapy rebound hyperbilirubinemia because data about bilirubin rebound in neonates are lacking and few studies have concerned this condition. A prospective observational study was conducted on 500 neonates with indirect hyperbilirubinemia who were treated according to standard guidelines. Total serum bilirubin (TSB) was measured at 24-36h after phototherapy; significant bilirubin rebound (SBR) is considered as increasing TSB that needs reinstitution of phototherapy. A total of 124 (24.9%) neonates developed SBR with TSB increased by 3.4 (2.4-11.2) mg/dL after stopping phototherapy. Multiple logistic regression model revealed the following significant risk factors for rebound: low birth weight (B=1.3, P< 0.001, OR 3.5), suspected sepsis (B=2.5, P< 0.001, OR 12.6), exposure to intensive phototherapy (B= 0.83, P= 0.03, OR 2.3), hemolysis (B= 1.2, P< 0.001, OR 3.1), high discharge bilirubin level (B= 0.3, P= 0.001, OR 1.3), and short duration of conventional phototherapy (B= -1.2, P< 0.001, OR 0.3). SBR should be considered in neonates with hemolysis, low birth weight, suspected sepsis, short duration of conventional phototherapy, exposure to intensive phototherapy, and relatively high discharge TSB. These risk factors should be taken into account when planning post-phototherapy follow-up.