Introduction Low surface contamination levels of hazardous drugs in compounding areas can be used as indicators of exposure and efficacy of cleaning procedures. We report the efficacy results of the KIRO® Oncology self-cleaning automated compounding system for decontamination of cytotoxic drugs, assessed in an oncology health center using a sanitizing method and an alkaline method. Methods The study was conducted for six-days over a three-week period. A mixture with known levels of 5-fluorouracil, ifosfamide, cyclophosphamide, gemcitabine, etoposide, methotrexate, paclitaxel, docetaxel and carboplatin was added to the KIRO® Oncology’s compounding area surface before each self-cleaning method was used. Contamination levels were determined, with a surface wipe sampling kit, at the end of the self-cleaning process. Results Background surface contamination for quantified levels of cytotoxic drugs during routine use of KIRO® Oncology was below limit of quantification (<LOQ) for all drugs, except for carboplatin, which has a very low LOQ (0.2 ng/sample). The quantified drug levels detected on surface wipe samples after self-cleaning using both methods in the KIRO® Oncology’s compounding area surface sections were all <LOQ when spiking with 1 ng/cm2 (ten times the ‘safe’ reference value), except for carboplatin (alkaline method only), although its levels were still below the ‘safe’ reference value (0.1 ng/cm2). For surface contamination levels when spiking with 100 ng/cm2, both self-cleaning methods had decontamination efficacies >99.8% for all cytotoxic drugs analyzed. Conclusion This study provides evidence on the efficacy of the KIRO® Oncology automatic self-cleaning system for surface area decontamination during the preparation of cytotoxic drugs.