Combined therapy with clarithromycin (CLTR) and N–acetyl cysteine (NAC) may be useful in diseases with impaired oxidant-antioxidant balance, fibroblast proliferation, and collagen deposition such as pulmonary fibrosis. Activated inflammatory cells which accumulate in the lower airways may release increased amounts of reactive oxygen species (ROS) when accompanied with a deficiency in glutathione, the major component of the lung antioxidant defense system, leading to lung injury and fibrosis. The aim of this study was to examine the combined effect of CLTR, and NNAC on bleomycin-induced lung fibrosis in rats. Bleomycin was administered by single intra tracheal instillation to Wistar rats to induce lung fibrosis. Rats under study were orally administered with NAC (3 mmol/Kg), and CLTR (20 mg/Kg) from day 4 to 21, after a single intra tracheal instillation of bleomycin (2.5 U/Kg) or saline on day 1. Combined treatment with CLTR and NAC significantly decreased the augmented collagen deposition in bleomycin exposed rats (P< 0.05). Hydroxyproline content was 1.711±0.94 mg/g/tissue, and 1.055±1.83 mg/g/tissue in bleomycin-treated (positive control), and CLTR + NAC treated rats, respectively. CLTR and NAC combined therapy resulted in a significant increase (P< 0.05) in GSH (22%), significant decrease (P< 0.05) in MDA (14%), and significant decrease (P< 0.05) in total protein levels (39%) when compared to positive control rats. The histological assessment using a semi quantitative score showed less collagen deposition, and inflammatory cells in CLTR + NAC treated rats compared to those receiving bleomycin alone. Additionally, hematological and clinical chemistry parameters of blood did not revealed any signs of toxicity of combined treatment. These results indicate that combined treatment with NAC and CLTR improves the pulmonary antioxidant protection, collagen deposition, and thus might be useful in reducing lung damage produced by bleomycin.