The authors estimate the relationship between the progression of honeycombing and disease activity of usual interstitial pneumonia (UIP) by open lung biopsy specimen and ground-glass opacity on thin-section computed tomography (CT). Open lung biopsy specimens and the initial and follow-up thin-section CT of 29 patients with proven UIP are reviewed. Follow-up thin-section CTs were performed from 2 to 61 months (mean, 15.3 months) after biopsy. The interval between the initial CT and open lung biopsy was from 2 to 30 days (mean, 10.0 days). Areas of ground-glass opacity and honeycombing were quantified respectively on each CT slice by using a 0%-100% scale with 10% increments. Each open lung biopsy specimen was scored semiquantitatively for alveolar desquamation, alveolar septal inflammation, inflammatory airway narrowing, obstructive pneumonitis, and lymphoid nodules. Patients were classified into either a mild or severe activity group according to the median value of the pathologic score and the median value of the area of ground-glass opacity. The authors compared the progression of honeycombing on follow-up thin-section CT between the groups. The progression of honeycombing in UIP was significantly faster in the severe activity group than in the mild group according to the pathologic score (p = 0.003) and the area of ground-glass opacity (p = 0.0024). In patients with UIP, more active inflammation of the pulmonary interstitium results in faster progression of honeycombing in long-term follow-up.