Objective: To determine accuracy of the clinical/radiological evaluation for diffuse pulmonary infiltrates compared with the pathological result of the surgical lung biopsy (SLB) and to evaluate the need for the latter in this setting. Methods: SLB was performed in 93 consecutive patients with diffuse interstitial lung diseases during the period from November 2002 to March 2008, through VATS in 53 patients or minithoracotomy in 40 patients. The presumptive diagnosis was based on clinical, radiological and non-invasive or minimally invasive diagnostic procedures and compared with the gold standard of histological diagnosis by SLB. Results: In 65 patients (69.9%) clinical/radiological evaluation reached a correct diagnosis, and in 28 (30.1%) a new diagnosis was obtained unexpectedly by the SLB. In usual interstitial pneumonia (UIP) sensitivity, specificity, positive and negative predictive values for the clinical/radiological diagnosis were 76.2%, 76.4%, 84.9% and 70.2% versus 58.8%, 76.2%, 58.8% and 76.2% respectively in other types. The post-test probability for the clinical/radiological evaluation was 90% in patients with UIP versus 77% in other diseases. Conclusions: Patients with typical clinical and radiologic features of UIP will usually not need to undergo biopsy. The other interstitial pneumonias usually cannot be distinguished on the basis of clinical and CT features, and thoracoscopic or open lung biopsy will usually be necessary if a precise histologic diagnosis is required.