Cofactors of HIV disease may be considered risk modifiers that are causally related to future disease course. The search for potential cofactors, of viral, host or environmental origin, may provide avenues for altering the natural history of HIV infection. Potential viral cofactors include viral strains, such as syncytium-inducing and nonsyncytium-inducing variants, and strains that are resistant to specific antiretroviral therapies. Although there is strong evidence that sexually transmitted diseases that lead to genital ulcers or abrasions are important cofactors of HIV transmission, their role as cofactors in HIV disease progression is less clear. Further study of agents such as human herpesviruses 6 and 8 and hepatitis C may shed light on the role of other infectious agents in progressive HIV disease. Far less research has been conducted on behavioural, genetic and sociodemographic factors that may influence HIV disease progression rates. Since current anti-HIV therapies do not offer a cure, but only a means of prolonging life, the identification of possible cofactors is critical.