Langerhans cell histiocytosis is a proliferative disorder of neoplastic Langerhans cells with activating mutations in the Erk signaling pathway. TP53 and U2AF1 mutations have been implicated in other myelomonocytic malignancies and we hypothesized that mutations in these genes may cosegregate in LCH patients according to BRAF mutation status. Towards this end, we collected cases with a pathologic diagnosis of Langerhans cell histiocytosis from Stanford University Hospital. We analyzed the status of known pathogenic alleles in BRAF, ARAF, TP53, U2AF1, and MAP2K1 on formalin-fixed, paraffin-embedded tissue by direct sequencing. A total of 41 cases (71%) had a BRAFV600E allele detected by sequencing. MAP2K1 mutations were also detected in 5 cases: 3 of 17 (18%) cases with wild-type BRAF and 2 of 41 (5%) cases with BRAFV600E mutations (P=0.14). No cases contained the previously reported ARAF mutation, Q347_A348del. All 10 cases with TP53 mutations contained mutant BRAFV600E allele (P=0.021). Of the 11 cases with U2AF1 mutated, 9 of 41 cases co-occurred with BRAFV600E mutations (P=0.31) and 2 of 17 with wild-type BRAF. Interestingly, we do not find that somatic activating MAP2K1 mutations are mutually exclusive with BRAFV600E mutations as has been reported previously. Instead, our data suggests that MAP2K1 mutations may be present along with BRAF either at diagnosis or may be acquired during disease progression. Furthermore, we demonstrated that likely deleterious TP53 mutations correlate with BRAF mutational status and may play a role in the underlying pathogenesis.