Porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV), a positive-strand RNA virus that belongs to the Arteriviridae family of Nidovirales, has been identified as the causative agent of PRRS. Nsp1α is the amino (N)-terminal protein in a polyprotein encoded by the PRRSV genome and is reported to be crucial for subgenomic mRNA synthesis, presumably by serving as a transcription factor. Before functioning in transcription, nsp1α proteolytically releases itself from nsp1β. However, the structural basis for the self-releasing and biological functions of nsp1α remains elusive. Here we report the crystal structure of nsp1α of PRRSV (strain XH-GD) in its naturally self-processed form. Nsp1α contains a ZF domain (which may be required for its biological function), a papain-like cysteine protease (PCP) domain with a zinc ion unexpectedly bound at the active site (which is essential for proteolytic self-release of nsp1α), and a carboxyl-terminal extension (which occupies the substrate binding site of the PCP domain). Furthermore, we determined the exact location of the nsp1α self-processing site at Cys-Ala-Met180↓Ala-Asp-Val by use of crystallographic data and N-terminal amino acid sequencing. The crystal structure also suggested an in cis self-processing mechanism for nsp1α. Furthermore, nsp1α appears to have a dimeric architecture both in solution and as a crystal, with a hydrophilic groove on the molecular surface that may be related to nsp1α's biological function. Compared with existing structure and function data, our results suggest that PRRSV nsp1α functions differently from other reported viral leader proteases, such as that of foot-and-mouth disease.