Here we present evidence that two non-homologous brain diseases-related genes, SERPINI1 and PDCD10, are tightly linked in a divergent configuration by a bidirectional promoter in an evolutionarily conserved fashion. Within their tiny intergenic region, a segment from nt 1 to 175 near the vicinity of PDCD10 was identified to function as a minimal promoter to efficiently drive the expressions of the two flanking genes. A critical regulatory fragment from nt 176 to 473 was further determined to contain a repressive element for SERPINI1 and an enhancer for PDCD10 that coordinately regulate the transcriptions of both genes. For all the non-homologous genes that have been described to be closely adjacent in the human genome, the intergenic region of the head-to-head PDCD10-SERPINI1 gene pair at 3q26 exhibits an interesting and informative example of a complex regulatory system that governs the expression of both genes not only through an asymmetric bidirectional promoter, but also through fine-tuned regulations with some cis-acting elements.