Background Diffuse parenchymal lung diseases (DPLDs) constitute a heterogeneous group of lung diseases characterized by variable degrees of inflammation and fibrosis. In some DPLD, significant morbidity and unfavorable prognosis, comparable to those of neoplastic diseases, are seen. Efficient and safe methods for the diagnosis of DPLD are needed. Aim of the work To assess the characteristic features of DPLD in Fayoum Governorate based on clinical, radiological, and functional assessment. Patients and methods This study included 100 patients with undiagnosed DPLD who were selected from the Chest Department, Fayoum University Hospital, during the period from June 2015 to June 2016. All patients were subjected to written informed consent, full medical history, echocardiography, collagen profile, arterial blood gas analysis, spirometry, 6 min walk test, high-resolution computed tomography (HRCT) of the chest and lung biopsy when indicated. Results Out of the 100 patients included in the study, 72 (72%) were women, 28 (28%) were men, 15 (15%) were smokers, and 73 (73%) had a history of raising birds. The mean age was 45.4 years(range, 8–85 years). HRCT showed different patterns of parenchymal affection. Idiopathic interstitial pneumonia was the predominant diagnosis (51%), followed by DPLD of known cause (33%), then granulomatous DPLD (12%), and lastly other rare forms of DPLD (4%). Conclusion The historical ‘gold standard’ of histological DPLD diagnosis is replaced by a ‘dynamic integrated approach’ using multidisciplinary discussion. The optimal HRCT technique for the evaluation of DPLD is crucial. HRCT of the chest was the diagnostic tool in 75% of the study patients without the need for biopsy.