This article uses an ecological-economic approach to study optimal investment in multi-species protection when species interact in an ecosystem. The analysis is based on a model of stochastic species extinction in which survival probabilities are interdependent. Individual species protection plans can increase a species’ survival probability within certain limits and contingent upon the existence or absence of other species. Protection plans are costly and the conservation budget is fixed. It is assumed that human well-being depends solely on the services provided by one particular species, but other species contribute to overall ecosystem functioning and thus influence the first species’ survival probability. One result is that it may be optimal to invest in the protection of those species that do not directly contribute to human well-being, even if biological conservation decisions are exclusively derived from such a utilitarian framework. Another result is that the rank ordering of spending priorities among different species protection plans, as obtained under the assumption of independent species, may be completely reversed by taking species interaction into account. The conclusion is that effective species protection should go beyond targeting individual species, and consider species relations within whole ecosystems as well as overall ecosystem functioning. Ecosystem health is identified as a necessary prerequisite for successful species protection in situ.