Bgl-II fragments of the genome of Herpes simplex virus type 2 (HSV-2) HG-52 were cloned into the vector p-Neo and were used to screen the complete HSV-2 genome for regions cross-hybridizing with the genome of HEL cells. Most extensive cross-hybridizing activity was observed with a 530 bp SstII subfragment of the viral BamHI G DNA-fragment (contained in Bgl II F), which spans the joint and the viral a-sequence. From a lambda-L47 library, a cellular 15 kb HindIII DNA fragment was subcloned in pBR 322 which contained a 1920 bp SstII subfragment having strong cross-hybridizing activity with the 530 bp Sst II fragment of HSV-2 BamHI G. Within this 1920 bp Sst II fragment the cross-hybridizing activity was confined to a 230 bp Bgl I/Hpa II subfragment. This 230 bp fragment (including the flanking sequences) was analyzed in comparison to the viral a-sequence. Sequence data revealed a (G + C) content of 66% in the cellular and 81% in the viral DNA fragment, which is mainly determined by an extremely (G + C) rich 16-fold direct repeat (DR2) at the 5'-end. The homology between both DNA-fragments varies between 56% and 79% within the L-S inversion region. Both sequences, furthermore, show homology to the human c-myc protooncogene.