Background: A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to: 1) estimate the maximum tolerated doses (MTD) or recommended phase II doses (RP2D) of veliparib and TMZ using the Continual Reassessment Method; 2) describe the toxicities of this regimen; and 3) evaluate plasma pharmacokinetics (PK) and peripheral blood mononuclear cell (PBMC) PARP inhibition after veliparib treatment. Methods: TMZ was given once daily and veliparib twice daily for 5 days, every 28 days. Five veliparib/TMZ dose levels were studied: 20/180; 15/180; 15/150; 20/135; and 25/135 mg/m²/dose, respectively. Baseline and serial veliparib PK samples were obtained on days 1 and 4. PBMC poly(ADP-ribose) (PAR) levels were also measured using an ELISA assay. A total of 12 subjects were enrolled at the RP2D. Results: Thirty-one patients (29 evaluable) with a median age of 7.0 years (range 1.3-19.8) were enrolled. Dose-limiting toxicities (DLT) included grade 4 neutropenia and thrombocytopenia at the 20/180 and 15/180 mg/m2/dose levels. Based on the toxicity profile, PKs and PBMC PAR results, the RP2D were veliparib, 25 mg/m² BID, and TMZ, 135 mg/m²/day, for 5 days every 28 days. No objective responses were observed, although 4 subjects had SD > 6 months duration, including one patient each with glioblastoma multiforme, anaplastic ependymoma, pilocytic astrocytoma, and optic pathway glioma. At the veliparib RP2D, the PK parameters included: Cmax, 1.2 ± 0.7 µM; AUC0-12 hr, 1.53 ± 0.61 µg•hr/mL; and Cl/F, 173 ± ml/min/m². PARP inhibition was observed in PBMC but did not correlate with veliparib dose levels. Conclusions: The combination of veliparib and TMZ was well tolerated in children with recurrent CNS tumors. Veliparib PK parameters at RP2D are similar to those in adults. PBMC PARP inhibition did not correlate with veliparib dose levels, perhaps due to the smaller number of patients at each dose level and the technical limitations of specimen collection/processing and the ELISA assay. A phase II trial of veliparib/TMZ in children with recurrent primary brain tumors is planned. Clinical trial information: NCT00946335.