The introduction of arsenic trioxide (ATO) in treatment of acute promyelocytic leukemia (APL) has resulted in high clinical complete remission (CR) rates over 90%. On the contrary, the risk for early death (ED) in APL patients treated with ATO continues to have a negative impact for optimization of APL therapeutics. There is an urgent need for precision medicine and biomarkers in clinical monitoring of ATO toxicity in APL, and ED in particular. This retrospective case series cohort proteomics study was conducted as a hypothesis generation effort and provides here several potential molecular leads on serum peptides expressed at different times after treatment with ATO in patients with APL. In 12 patients with a de novo APL diagnosis, and treated with single-agent ATO as frontline remission induction therapy, serum peptides were fractionated by weak cation exchange magnetic beads and analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Ten peptides (m/z 2075.5, 2084.2, 2203.0, 2265.2, 2872.8, 2916.6, 3145.2, 3153.4, 3953.4, and 3964.8) were significantly downregulated in serum after ATO treatment. Among them, four peptides were identified as (1) Immunoglobulin heavy chain V-III region BUT, (2) RRP15-like protein, (3) filaggrin, and (4) protein SON isoform F. To the best of our knowledge, this is the first clinical oncology proteomic biomarker study with a view to future rational therapeutic monitoring of patients with APL in the course of single-agent ATO treatment and hematological CR.Keywords: acute promyelocytic leukemia; arsenic trioxide; biomarkers; precision medicine; proteomics; therapeutic drug monitoring.