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For nontransmissible diseases, decisions between interventions focused on high-risk groups and unfocused interventions can be based on attributable-risk calculations. The assumptions of those calculations, however, are violated for infectious diseases.We used deterministic compartmental models of infection transmission having both high- and low-risk groups and both susceptible and infected states to examine intervention effects on endemic infection levels. High risk is generated by increased susceptibility or contagiousness—factors that can be reduced by interventions. Population effects of focused and unfocused interventions are compared at settings where these would be equal if there were no transmission.In the most likely range of mixing between high- and low-risk groups, focused interventions have considerably larger effects than unfocused interventions. At all mixing levels, both interventions have greater effects on infectious than noninfectious diseases because a change in risk factor for one individual alters risk in others. Interventions on contagiousness in high-risk groups have greater effects than comparable interventions on susceptibility.Risk assessment for infectious disease requires analysis of the population system that is circulating the infection. Vaccine trials on individuals will miss important effects that trials on transmission units will detect. Focusing HIV control on contagiousness factors in high-risk groups will be especially productive.