Occupational exposure of anticancer agents during their preparation has been recognized as a serious hazard. Closed system drug transfer devices (CSTDs) enable “safe” preparation of agents for medical personnel and ensure a safe hospital environment. However, artificial particles of infusion materials have been reported during CSTD use. Here, the incidence of insoluble fine particles during preparation of anticancer agents using CSTDs was examined. Visible insoluble fine particles were found in 465 (9.4%) of 4,948 treatment cases at Ehime University Hospital with CSTD use. Contaminants occurred more frequently during preparation of monoclonal antibodies than cytotoxic anticancer agents (19.4% versus 4.1%, respectively, P<0.01). A similar survey was conducted at nine hospitals to investigate the incidence of insoluble fine particles with or without CSTDs. Insoluble fine particles were detected in 113 (15.4%) of 732 treatment cases during preparation of monoclonal antibodies with CSTD use. In contrast, the occurrence of insoluble fine particles without CSTDs was found in only 3 (0.073%) of 4,113 treatment cases. Contamination with CSTDs might cause harmful effects on patients 4 during cancer therapy. We strongly recommend the use of in-line filters combined with infusion routes after CSTD use to avoid contamination-associated adverse events.