Acute promyelocytic leukemia (APL) is highly malignant and progresses rapidly. In recent years, several studies have shown that oral arsenic, the primary component is realgar, could effectively alleviate APL, with therapeutic effects not inferior to those of intravenous arsenic and a higher safety profile, but currently the active substances and mechanism of realgar's anti-APL effect are unclear, making oral arsenic agents containing realgar lack sufficient scientific basis clinically. The clinical trials on oral arsenic agents containing realgar for the treatment of APL over the past 20 years were reviewed, suggesting it had good therapeutic effect and relatively high safety. Quantitative analysis was conducted on the accumulation of arsenic metabolites in different tissues during the longest 90 day period after realgar administration in rats, and it was found that dimethylarsenic (DMA) was the most predominant form of arsenic metabolites in the body. The DMA concentration slightly increased and remained stable with prolonged administration time, even if discontinuation, the DMA concentration still remained at a certain level. Distribution and accumulation of DMA were significantly higher in blood than in organs. Futhermore, DMA significantly prolonged the survival time of APL mice, induced cell apoptosis, inhibited NB4 cell proliferation, promoted the differentiation of leukemia cells, and downregulated the expression of PML-RARα fusion protein and wild-type RARα protein. The study concluded that DMA could be the main active substance of realgar and is responsible for its significant anti-APL effects, suggesting realgar has good efficacy for blood-related diseases and have low hepatorenal toxicity.