Li-Fraumeni syndrome (LFS) is one of the familial cancers characterized by different tumors and hereditary TP53 mutations. The adrenocortical carcinoma (ACC) association with acute leukemia is unusual in childhood, even in LFS. The authors here present a family with pR337P mutation in TP53 gene who had a child with acute lymphoblastic leukemia (ALL) and associated adrenocortical carcinoma as a case 1 and his cousin with brain tumor as a case 2. A hereditary TP53 mutation supported the diagnosis of LFS in this family. The patients had many difficulties in treatment strategies and succumbed to death. The availability of a reliable molecular marker to detect the R337P TP53 mutation allows the rapid identification of carriers in families that have a child with ACC. Once identified, carriers could be screened for early detection of ACC by imaging and endocrine studies and should be given psychological support to prevent anxiety for death. Whether early detection of ACC will reduce the mortality in these patients remains to be determined.