Hearing loss is the most frequent long-term complication of pneumococcal meningitis, affecting up to 40% of survivors. Unfortunately, adjuvant therapy with dexamethasone has failed to satisfactorily reduce its incidence. Therefore, we evaluated the use of antioxidants for the adjunctive therapy of meningitis-associated deafness. Eighteen hours after intracisternal injection of 7.5 × 105 colony-forming units of Streptococcus pneumoniae, rats were treated systemically either with ceftriaxone and the antioxidants and peroxynitrite scavengers Mn(III)tetrakis(4-benzoic acid)-porphyrin (MnTBAP) or N-acetyl-L-cysteine (NAC) or placebo (1ml phosphate-buffered saline) for 4 days. Hearing was assessed by auditory brainstem response audiometry. Adjunctive antioxidant therapy significantly reduced the long-term hearing loss (14 days after infection) for square wave impulses (mean hearing loss ± SD: ceftriaxone and placebo, 45±26dB; ceftriaxone and MnTBAP, 9±23dB; ceftriaxone and NAC, 19±30dB) as well as 1kHz (ceftriaxone and placebo, 28±19dB; ceftriaxone and MnTBAP, 10±16dB; ceftriaxone and NAC, 10±17dB), and 10kHz tone bursts (ceftriaxone and placebo, 62±27dB; ceftriaxone and MnTBAP, 16±13dB; ceftriaxone and NAC, 25±26dB). Furthermore, both antioxidants attenuated the morphological correlates of meningogenic hearing loss, namely, long-term blood-labyrinth barrier disruption, spiral ganglion neuronal loss, and fibrous obliteration of the perilymphatic spaces. Adjuvant antioxidant therapy is highly otoprotective in meningitis and therefore is a promising future treatment option.