Therapeutic drugs such as the aminoglycoside antibiotics (AMG) and the chemotherapy agent cisplatin (CDDP) are known to cause irreversible hearing loss, typically affecting highest frequency hearing first with progression of loss to the lower frequency regions. Conventional (0.25-8 kHz) and high-frequency (9-20 kHz) serial hearing threshold monitoring was done in 123 hospitalized patients (222 ears) administered AMG or CDDP. Of ears showing a decrease in sensitivity corresponding with treatment, 62.5% demonstrated initial hearing loss solely in the high-frequency range, 13.5% first showed loss only in the conventional-frequency range, and 24.0% showed loss in both frequency ranges concurrently. Thus, if only high frequencies had been monitored, early change in auditory sensitivity would have been detected in 86.5% of these patients. Further analysis revealed a range of five frequencies, specific to each individual's hearing threshold configuration, in which initial ototoxicity appeared most likely to be detected. Testing only these five frequencies would have identified 89.2% of ears that showed change. The results of this study confirm the need to serially monitor auditory thresholds, especially in the high-frequency range, of patients receiving ototoxic drugs. A shortened five-frequency monitoring protocol is presented and suggested for use with patients unable to tolerate lengthy audiometric testing procedures.