Objectives The aims of the study were to evaluate the external contamination of hazardous drug vials used in Chinese hospitals and to compare environmental contamination generated by a robotic intelligent dispensing system (WEINAS) and a manual compounding procedure using a biological safety cabinet (BSC). Methods Cyclophosphamide, fluorouracil, and gemcitabine were selected as the representative hazardous drugs to monitor surface contamination of vials. In the comparative analysis of environmental contamination from manual and robotic compounding, wipe samples were taken from infusion bags, gloves, and the different locations of the BSC and the WEINAS robotic system. In this study, high-performance liquid chromatography coupled with double mass spectrometer (HPLC-MS/MS) was employed for sample analysis. Results (1) External contamination was measured on vials of all three hazardous drugs. The contamination detected on fluorouracil vials was the highest with an average amount up to 904.33 ng/vial, followed by cyclophosphamide (43.51 ng/vial), and gemcitabine (unprotected vials of 5.92 ng/vial, protected vials of 0.66 ng/vial); (2) overall, the environmental contamination induced by WEINAS robotic compounding was significantly reduced compared to that by manual compounding inside the BSC. Particularly, compared with manual compounding, the surface contamination on the infusion bags during robotic compounding was nearly nine times lower for cyclophosphamide (10.62 ng/cm2 vs 90.43 ng/cm2), two times lower for fluorouracil (3.47 vs 7.52 ng/cm2), and more than 23 times lower for gemcitabine (2.61 ng/cm2 vs 62.28 ng/cm2). Conclusions The external contamination occurred extensively on some hazardous drug vials that commonly used in Chinese hospitals. Comparison analysis for both compounding procedures revealed that robotic compounding can remarkably reduce environmental contamination.