C4.4A is a structural homologue of the urokinase-type plasminogen activator receptor (uPAR), which, through its involvement in pathogenic plasminogen activation, is a well-consolidated prognostic marker in a variety of human cancers. Although the biological function of C4.4A remains elusive, the protein has been implicated in cancer invasion and metastasis, possibly playing a role in cell/cell or cell/matrix interactions. Particularly interesting observations have been made on the expression of C4.4A in non-small cell lung cancer (NSCLC). An immunohistochemical, retrospective study was performed on formalin-fixed, paraffin-embedded specimens from 104 patients, including 56 squamous cell carcinomas (SCC), 40 adenocarcinomas (AC) and 8 large cell carcinomas (LCC). Whereas normal lung tissue was negative for C4.4A, high levels were found in 77 % of SCC, 24 % of AC and 13 % of LCC, thus correlating C4.4A expression to histological type of NSCLC. Staining with a well-characterized polyclonal anti-C4.4A antibody was either confined to invasive areas of the tumor or present in all cancer cells. Survival data displayed a correlation between high C4.4A expression and overall mortality in NSCLC patients (P=0.012). Intriguingly, a closer examination of these data revealed that the subgroup of patients having high C4.4A expression combined with a histological classification as adenocarcinoma had a particularly poor survival (P < 0.0001), all patients dying within 2 years. This is the first demonstration of a very strong prognostic significance of C4.4A in NSCLC, with a predominant impact on patients with AC. Preliminary data furthermore show that C4.4A might be a marker of premalignant lesions of NSCLC.