The efficacy of three different doses of sodium salicylate (SAL) in combination with one dose of N-acetylcysteine (NAC) to prevent noise-induced hearing loss was studied in chinchillas. After obtaining baseline-hearing thresholds, the chinchillas were randomly assigned to one of four treatment groups: three sets were injected intraperitoneally with 325 mg/kg NAC combined with 25, 50, or 75 mg/kg SAL, and a separate control group was injected with an equal volume of saline. Animals were injected twice daily for 2 days prior to and 1 hour before the noise exposure (6 hours to a 105-dB Standard Pressure Level octave band noise centered at 4 kHz). Immediate post-noise hearing thresholds were obtained followed by post-noise treatments at 1 hour then twice-daily for 2 days. Hearing tests continued at 1, 2, and 3 weeks post-noise, and immediately after the last hearing test, animals' cochleae were stained for hair cell counts. All the groups showed hearing improvement until week 2. However, at week 3, saline treated animals demonstrated a 17-33 dB SPL permanent threshold shift (PTS) across the test frequencies. Hearing loss was lowest in the 50 SAL/325 NAC mg/kg group (all frequencies, P < 0.001), and although PTS was reduced in the 25 and 75 mg/kg SAL dosage groups compared to the saline group, only the 75 mg/kg SAL group was significantly different at all but 2 kHz frequency. Coupled with the hearing loss, outer hair cell (OHC) loss was maximal in the 4-8 kHz cochlear region of saline treated animals. However, there was a substantial reduction in the mean OHC loss of the NAC plus 50 or 75 mg/kg (but not the 25 mg/kg) SAL groups. These findings suggest that SAL in combination with NAC is effective in reducing noise damage to the cochlea, but SAL has a relatively narrow therapeutic dosing window.