Arsenic trioxide (As(2)O(3)) is highly efficacious for acute promyelocytic leukemia (APL). Environmental arsenic exposure predisposes to malignancies, but the risk for therapeutic arsenic is undefined. Three APL patients (de novo, 2; therapy-related, 1) in a cohort of 59 cases given oral-As(2)O(3) for induction and maintenance treatment developed secondary cancers (nasopharyngeal carcinoma, 2; colonic adenocarcinoma, 1) at 16, 36 and 55 months post-As(2)O(3) therapy. Retrospective analysis of biomarkers (Epstein Barr virus serology and quantification, carcinoembryonic antigen) showed the potential presence of cancers before or shortly after As(2)O(3) therapy, suggesting that As(2)O(3) had not initiated these malignancies. Compared against matched background population, there was an increased risk of second cancer (p=0.012, standard incidence ratio=6.5; 95% confidence interval=1.4-19.0).