OBJECTIVES: The importance of identifying non-small cell lung cancer (NSCLC) histological subtype has increased recently because of the need to target high cost therapeutic agents to the correct patient population. This systematic review was undertaken to examine the diagnostic accuracy of histology in differentiating between sub-types of NSCLC, specifically the ability to differentiate squamous from non-squamous histology.  METHODS: A systematic literature search was undertaken to identify studies that evaluated the reproducibility of histologic diagnosis by pathologists in their reporting of NSCLC sub-types. Studies were screened systematically using a priori defined eligibility criteria. The National Health and Medical Research Council (NHMRC) diagnostic levels of evidence were applied, and quality assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. Data were extracted and re-analysed to permit comparison of agreement in non-squamous and squamous cell carcinoma via 2x2 tables. Pooled diagnostic performance measures including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) were calculated, with the PPV being considered the most relevant indicator for the treating clinician. RESULTS: Out of 1480 articles identified through the literature search, seven were eligible for inclusion. The PPV of non-squamous histology was consistently high in each individual study with only a small amount of variation between studies. This resulted in a very high pooled PPV of 95.3% (94.0%–96.3%) for the primary meta-analysis. CONCLUSIONS: The high individual and pooled PPV suggests that pathologists can reliably differentiate between non-squamous and squamous NSCLC. This is important in guiding oncologist decision making in choosing the most appropriate therapy for their patients. It is also significant from a purchaser perspective; because it will limit cost leakage from prescriptions mistakenly given outside the drugs approved indication (i.e. to the incorrect NSCLC patient group) due to misdiagnosis.