N-Acetyl-L-cysteine (NAC), 50, 100, 200, or 400 mg/kg, was injected intraperitoneally once a day for 13 days. No change was seen in the total sulfhydryl (TSH) and nonprotein sulfhydryl (NPSH) contents of the liver, kidney, and plasma at any dose. The heart TSH level remained unchanged, but the NPSH level was increased from the control value of 16 nmol/mg to 18, 19, and 18 nmol/mg protein at 50, 100, and 200 mg/kg, respectively. The lung TSH and NPSH levels both were increased from the control values of 65 and 8 nmol/mg to 80 and 16 nmol/mg protein, respectively, at 200 mg/kg. The lung TSH level at 400 mg/kg NAC was not changed, but the NPSH level increased to 13.5 nmol/mg protein. The ratio of TSH to NPSH levels in the liver and kidney was 4:1, whereas in the lung and heart it was 7:1 and 8:1, respectively. Based on amount per milligram of protein, TSH and NPSH levels were highest in the liver, followed by the amounts in the kidney, heart, and lung. The lung had the lowest level of TSH and NPSH. The daily treatment with NAC (200 mg/kg) for 13 days after and 2 days before intratracheal injection of bleomycin (7.5 U/kg) had little effect on lung collagen accumulation. The lung collagen level measured as hydroxyproline in bleomycin and in NAC plus bleomycin was significantly increased to 175% and 183% of the control levels, respectively. There was no difference in the lung hydroxyproline content between the control and NAC groups. The histopathology study also revealed no marked difference between the bleomycin and bleomycin plus NAC groups. Alternatively, treatment with NAC (200 mg/kg) for 13 days before bleomycin made the animals more susceptible to bleomycin toxicity and tended to add to the bleomycin-induced accumulation of collagen in the lung. NAC per se caused no mortality at any dose. The lung TSH and NPSH levels in bleomycin-treated (7.5 U/kg) hamsters were increased to 136% and 111% of control, respectively, whereas the TSH and NPSH levels both were increased to 155% of the levels of their respective controls in hamsters in the NAC plus bleomycin group. The differential effects of NAC treatment on the sulfhydryl content of tissues, the treatment's inability to alter the course of bleomycin-induced lung inflammation and collagen accumulation, and the potential for exacerbation of lung toxicity in response to repeated administration of NAC before exposure to fibrogenic agents are discussed.