Objectives: The Scleroderma Lung Study showed the efficacy of cyclophosphamide in modestly improving the forced vital capacity (FVC) compared with placebo over 1 year. Using changes in texture-based scores that quantify lung fibrosis as the percentage involvement of reticulation patterns, the effectiveness of cyclophosphamide was re-assessed by examining its impact on quantitative lung fibrosis (QLF). Methods: Axial HRCT images were acquired (1-mm slice thickness, 10-mm increments) in the prone position at inspiration. A validated model for quantifying interstitial disease patterns was applied to images from 83 subjects at baseline and 12 months. Scores were calculated for six zones (upper, mid, lower of the right/left lung) and the whole lung. Average changes were compared. Correlations were performed between QLF and physiological and clinical scores. Results: From the most severe zones identified at baseline, QLF scores decreased by 2.6% in the cyclophosphamide group, whereas they increased by 9.1% in the placebo group, leading to ~12% difference (p∈=∈0.0027). Between-treatment difference in whole lung QLF was ~5% (p∈=∈0.0190). Significant associations were observed between changes in QLF and FVC (r∈=∈-0.33), dyspnea score (r∈=∈-0.29), and consensus visual score (p∈=∈0.0001). Conclusions: QLF scores provide an objective quantitative tool for assessing treatment efficacy in scleroderma-related interstitial lung disease. © 2011 European Society of Radiology.