BACKGROUND: It has been hypothesized that genetic alteration at the cellular level may have a significant effect on cellular mechanisms controlling the proliferation and apoptosis of Langerhans cells (LCs). METHODS: We examined whether p16 protein expression can be used to predict the outcome of Langerhans cell histiocytosis (LCH). Archival paraffin blocks from children diagnosed with LCH and followed at the Asan Medical Center and Chungnam National University Hospital between March 1998 and February 2008 were studied. RESULTS: Slides were stained with p16 antibody and evaluated semi-quantitatively using the following scale: negative, no staining; +/-, weakly positive; 1+, staining similar to lymphocytes surrounding the LCs; 2+, stronger staining than lymphocytes; 3+, much stronger staining than lymphocytes. Negative and +/- groups were assigned to a lower expression group (LEG) and the 1+, 2+, and 3+ groups were assigned to a higher expression group (HEG). The median age of the 51 patients (24 girls, 27 boys) was 49 (range, 0.6-178) months, and LCH was diagnosed based on CD1a positivity. p16 protein was expressed to varying degrees in all but one specimen. There was a greater tendency toward multisystem disease, risk organ involvement, and relapse in the HEG than in the LEG. CONCLUSION: The p16 protein may have a significant effect on cellular mechanisms controlling the proliferation and apoptosis of LCs, and thus may influence the clinical outcome and prognosis of LCH.