The goal of this study was to seek indirect evidence that smoking is an aetiological factor in some patients with non-specific interstitial pneumonia (NSIP). Ten current and eight ex-smokers with NSIP were compared to controls including 137 current smokers with no known interstitial lung disease and 11 non-smokers with NSIP. Prevalence and extent of emphysema in 18 smokers with NSIP were compared with subjects meeting GOLD criteria for chronic obstructive pulmonary disease (COPD; group A; n = 34) and healthy smokers (normal FEV(1); group B; n = 103), respectively. Emphysema was present in 14/18 (77.8%) smokers with NSIP. Emphysema did not differ in prevalence between NSIP patients and group A controls (25/34, 73.5%), but was strikingly more prevalent in NSIP patients than in group B controls (18/103, 17.5%, P < 0.0005). On multiple logistic regression, the likelihood of emphysema increased when NSIP was present (OR = 18.8; 95% CI = 5.3-66.3; P < 0.0005) and with increasing age (OR = 1.04; 95% CI = 0.99-1.11; P = 0.08). Emphysema is as prevalent in smokers with NSIP as in smokers with COPD, and is strikingly more prevalent in these two groups than in healthy smoking controls. The association between NSIP and emphysema provides indirect support for a smoking pathogenesis hypothesis in some NSIP patients.