Carboplatin is the most commonly used drug in the first-line treatment of human retinoblastoma (RB), but its clinical application is greatly limited due to acquired drug resistance upon the long-term treatment. Forkhead box protein M1 (FoxM1) is the transcription factor aberrantly expressed in various types of human cancers, which plays an essential role in the regulation of tumorigenesis, tumor metastasis and drug resistance. However, little is known about the role of FoxM1 in chemo-resistance of human RB. In this study, we investigated the regulatory effect of FoxM1 on carboplatin resistance in human RB Y-79 cells and carboplatin-resistant Y-79 (Y-79CR) cells, as well as the possible mechanism. Our results showed that FoxM1 was up-regulated in Y-79CR cells and silencing of FoxM1 promoted carboplatin sensitivity and accumulation, while overexpression of FoxM1 in Y-79 cells performed oppositely. Our study further revealed that FoxM1 enhanced carboplatin resistance in Y-79CR cells through directly up-regulating the transcription of ATP-binding cassette transporter C4 (ABCC4), an important drug efflux transporter. Overall, our study demonstrated the novel role of FoxM1-ABCC4 axis in human RB, which provides insights into the prevention of carboplatin resistance in human RB.