Background:The pro-inflammatory cytokine migration inhibitory factor (MIF) and its receptor CD74 have been proposed as possible therapeutic targets in several cancers. We studied the expression of MIF and CD74 together with calretinin in specimens of malignant pleural mesothelioma (MPM), correlating their expression levels with clinico-pathologic parameters, in particular overall survival (OS).Methods:Migration inhibitory factor, CD74, and calretinin immunoreactivity were investigated in a tissue microarray of 352 patients diagnosed with MPM. Protein expression intensities were semiquantitatively scored in the tumour cells and in the peritumoral stroma. Markers were matched with OS, age, gender, and histological subtype.Results:Clinical data from 135 patients were available. Tumour cell expressions of MIF and CD74 were observed in 95% and 98% of MPM specimens, respectively, with a homogenous distribution between the different histotypes. CD74 (P<0.001) but not MIF overexpression (P=0.231) emerged as an independent prognostic factor for prolonged OS. High expression of tumour cell calretinin correlated with the epithelioid histotype and was also predictive of longer OS (P<0.001). When compared with previously characterised putative epithelial-to-mesenchymal transition markers, CD74 correlated positively with tumoral PTEN and podoplanin expressions, but was inversely related with periostin expression.Conclusions:High expression of CD74 is an independent prognostic factor for prolonged OS in mesothelioma patients.