Preservatives are an important component of ophthalmic preparations, providing antimicrobial activity in the bottle and preventing decomposition of active drug. Often underrecognized, however, are the significant cytotoxic effects of preservatives associated with long-term therapy and especially use of multiple preserved drugs. The most common preservatives in ophthalmic preparations for glaucoma and surface eye disease-benzalkonium chloride (BAK), chlorobutanol, sodium perborate, and stabilized oxychloro complex (SOC)-were reviewed. Compared with other preservatives, SOC caused the least amount of damage to rabbit corneal epithelial cells. BAK has demonstrated cytotoxic effects in cell culture, as well as in animal and human studies. Physicians should consider treatment with new-generation preparations containing low-risk preservatives such as SOC, especially in patients receiving multiple ophthalmic medications.