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Glutaraldehyde, a chemical associated with respiratory illness, has been used for high-level disinfection in hospitals for 40 years. Two substitutes have recently been introduced—ortho-phthalaldehyde and a mixture of hydrogen peroxide and peracetic acid—despite limited health effects information about the products. This project used a two-tiered approach to evaluate the risks associated with substitution of high-level disinfectants. It involved predicting the relative toxic effects of all the products and assessing the current practices regarding the use of high-level disinfectants in British Columbia hospitals. Relative potential toxicities were examined based on regulatory data, a review of the published literature, and a qualitative structure-activity relationship analysis. There was no published literature and little regulatory data available for orthophthalaldehyde and there is no history of using ortho-phthalaldehyde solutions in any industry. Structure-activity results suggest ortho-phthalaldehyde has dermal and respiratory sensitizing potential. Although little epidemiological data was available for hydrogen peroxide or peracetic acid, structure-activity analysis results suggest little risk of sensitization. Current practices in industry were assessed using a comprehensive survey of current practices and decision processes in all hospitals in British Columbia. Of 95 hospitals, 64 returned surveys; 80% of these used high-level disinfection. Among user hospitals, 49% used glutaraldehyde only and 51% had introduced alternatives. Concern about employee health was the most common reason for substituting but was frequently not considered when choosing specific alternatives. Although occupational health and safety staff were available to 67% of user hospitals, they were involved in the decision process about the use of chemical high-level disinfectants in only 41%. Hospitals that involved occupational health, infection control, or regional staff in high-level disinfectant decisions used glutaraldehyde alternatives less frequently. In most hospitals it was difficult to find any one person knowledgeable about the use of disinfectants at the site. Despite the fact that little is known about the risks to employees from glutaraldehyde alternatives, their use is widespread. The potential risks of all high-level disinfectants are serious; thus, regulators are faced with important risk management decisions not only before introducing new chemicals, but also after they have been introduced into the workplace.