Aims: The accurate diagnosis of malignant pleural mesothelioma (MPM) is essential for therapeutic and legal reasons. In 2006 the International Mesothelioma Panel advocated the use of a panel, including two mesothelial and two non-mesothelial immunohistochemical (IHC) markers. We assessed the changing use of IHC for the diagnosis of MPM in Australia over two decades in the context of current best practice. Methods: Patients with a confirmed clinico-pathological diagnosis of MPM who underwent extrapleural pneumonectomy or pleurectomy and/or decortication between 1988 and 2006 were identified from the cardiothoracic database at Royal Prince Alfred Hospital and combined with consecutive patients reviewed by the Dust Diseases Board between March 2007 and March 2009. Initial diagnostic pathology reports were reviewed. Results: A total of 289 patients were identified. A median of six IHC stains per sample was performed (range 0-18): two (range 0-5) mesothelial markers, two (0-6) carcinoma markers and two epithelial markers. A trend to the higher usage of antibodies in epithelioid tumors versus biphasic and sarcomatoid tumors was noted (P=0.148 and 0.389, respectively). Testing increased from a median of three stains per sample (1988-1997) to seven (2006-2009). Labeling specimens with >2 mesothelial markers and >2 carcinoma markers increased to 72 and 67 percent, respectively, after 2006. Conclusion: Reflecting the acceptance of diagnostic panels and increased availability of antibodies, an increase in the use of IHC stains for MPM diagnosis has occurred over the past two decades although uncertainty persists as to the optimal panel composition.