Background: Dosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients. Methods: We designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug’s target concentration, regardless of a patient’s pharmacokinetics (PK). Findings: We demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that mimic the PK variability observed clinically. In one set of experiments, BSA-based dosing resulted in a concentration 7 times above the target range, while CLAUDIA keeps the concentration of 5-FU in or near the targeted range. Further, we demonstrate that CLAUDIA is cost effective compared to BSA-based dosing. Conclusions: We anticipate that CLAUDIA could be rapidly translated to the clinic to enable physicians to control the plasma concentration of chemotherapy in their patients.