RATIONALE: In the absence of a surgical lung biopsy, patients diagnosed with idiopathic pulmonary fibrosis (IPF) in clinical practice could participate in the INPULSIS® trials of nintedanib if they had honeycombing and/or traction bronchiectasis plus reticulation, without atypical features of usual interstitial pneumonia (UIP), on high-resolution computed tomography (HRCT). Thus the patients in these trials represented patients with definite UIP and a large subgroup of patients with possible UIP. OBJECTIVE: We investigated the potential impact of diagnostic subgroups on the progression of IPF and effect of nintedanib. METHODS: Post-hoc subgroup analysis of patients with honeycombing on HRCT and/or confirmation of UIP by biopsy versus patients without either, using pooled data from the INPULSIS® trials. MEASUREMENTS AND MAIN RESULTS: 723 (68.1%) patients had honeycombing and/or biopsy and 338 (31.9%) had no honeycombing or biopsy. In these subgroups, respectively, the adjusted annual rate of decline in forced vital capacity (FVC) in patients treated with placebo was -225.7 mL/year and -221.0 mL/year, and the nintedanib versus placebo difference in adjusted annual rate of decline in FVC was 117.0 mL/year (95% CI: 76.3, 157.8) and 98.9 mL/year (95% CI: 36.4, 161.5). There was no significant treatment-by-subgroup interaction (p=0.8139). Adverse events were similar between subgroups. CONCLUSION: Patients with IPF diagnosed in clinical practice who have possible UIP with traction bronchiectasis on HRCT and have not undergone surgical lung biopsy have disease that progresses in a similar way, and responds similarly to nintedanib, as patients with honeycombing on HRCT and/or confirmation of UIP by biopsy. Clinical trial registration available at www.clinicaltrials.gov, IDs NCT01335464 and NCT01335477.