Chronic (fibrotic) hypersensitivity pneumonitis (HP) and fibrosing interstitial pneumonias associated with connective tissue disease (CTD-ILD) can be difficult to distinguish in biopsy specimens. To investigate features that might separate these entities, 2 pathologists blinded to the diagnoses reviewed 16 cases of chronic HP and 12 cases of CTD-ILD. Fifteen predefined parameters were examined by morphometric point counting, analysis/cm of lung tissue, or presence/absence. Germinal centers were present in a minority of patients, but favored a diagnosis of CTD-ILD (7/12 CTD vs. 2/16 HP; odds ratio, 9.80 [95% confidence interval, 1.50-63.4]; P=0.02). The number of lymphoid aggregates/cm (4.4±3.1 vs. 1.4±1.0; P=0.001), volume proportion of plasma cells (0.076±0.058 vs. 0.031±0.023; P=0.031), and plasma cell: lymphocyte ratio (1.03±0.71 vs. 0.35±0.22; P=0.001) were all significantly higher in CTD compared with HP. A diagnosis of HP was more common in the presence of peribronchiolar metaplasia (12/16 HP vs. 4/12 CTD; odds ratio, 6.00 [95% confidence interval, 1.15-31.2]; P=0.033) and in patients with a greater fraction of bronchioles showing peribronchiolar metaplasia (0.41±0.33 vs. 0.16±0.27; P<0.001). Number of fibroblast foci/cm, distribution of fibroblast foci, pattern of fibrosis, presence of giant cells/granulomas, and volume proportion of lymphocytes or eosinophils did not distinguish chronic HP from CTD-ILD. We conclude that no single morphologic measure definitively separates chronic HP from CTD-ILD lung biopsies, but numerous foci of peribronchiolar metaplasia favor HP, while the presence of germinal centers, large numbers of lymphoid aggregates, or a high plasma cell: lymphocyte ratio suggests CTD-ILD. Multidisciplinary discussion is often necessary for accurate classification inthis setting.