Small cell lung cancer (SCLC) is characterised by early and widespread metastasis. However, SCLC cells have so far been found to produce low levels of known pro-angiogenic factors. We speculated that SCLC cells might produce alternative pro-angiogenic factors. Here, we report that a panel of SCLC cell lines constitutively secrete granulocyte chemotactic protein-2 (GCP-2)/CXCL6, a CXC ELR+ chemokine. In contrast, none of the three tested NSCLC cell lines secreted GCP-2. Production of GCP-2 in vivo was also confirmed in seven out of nine specimens with SCLC. We demonstrate that expression of GCP-2 is mediated by NF-kappaB as ALLN, an NF-kappaB pathway inhibitor, almost completely abolished GCP-2 production in SCLC cell lines. We also demonstrate that GCP-2 can be significantly upregulated by IL-1beta and hypoxia in SCLC cell lines. This result suggests a role for GCP-2 in promoting tumour progression in vivo under unfavourable conditions such as oxygen deprivation. As SCLC cells express both GCP-2 and its receptors CXCR1 and CXCR2, their biological significance in SCLC progression was further studied. We demonstrate that GCP-2 is an autocrine growth factor. Cell proliferation was significantly inhibited by anti-GCP-2 neutralising antibody in two high-GCP-2-producing cell lines. In addition, expression of the proliferation marker PCNA was upregulated by exogenous GCP-2 in two low-GCP-2-producing cell lines. Taken together, these results suggest an important role for GCP-2 as an autocrine mitogen in the growth and metastasis of SCLC.