Background: Idarubicin, a PO bioavailable anthracycline antibiotic-class chemotherapeutic, could have substantial convenience advantages over currently available similar class agents in use that require IV delivery. Objectives: The primary objective of this study was to determine the maximally tolerated dose (MTD), dose-limiting toxicities (DLTs), and basic pharmacokinetic parameters of oral idarubicin exposure in dogs with lymphoma after a single oral dose. A secondary objective was to document preliminary antitumor efficacy in an expanded treatment cohort using the established MTD. Animals: Client-owned dogs with measurable lymphoma. Methods: Dogs (n = 31) were enrolled in a prospective open label phase I study of oral idarubicin. By means of a 3 + 3 cohort design, dose escalations were made with 3 dogs per dose level, and the MTD was established based on the number of patients experiencing a DLT. Plasma concentrations of idarubicin and idarubicinol were determined by postdose sampling. Assessment of antitumor efficacy focused on evaluation of accessible, measurable lymph nodes and skin lesions by modified RECIST guidelines. Results: The MTD in dogs > 15 kg body weight was 22 mg/m 2. Adverse hematologic events (neutropenia and thrombocytopenia) were the predominant DLT and generally correlated with higher plasma concentrations of idarubicin and idarubicinol. Conclusions and Clinical Importance: PO administered idarubicin was generally well-tolerated and had preliminary antitumor activity in dogs with lymphoma. Furthermore, the potential clinical advantage of a safe and efficacious oral anthracycline alternative supports further investigations of this agent in repeated-dose, randomized clinical trials.