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Procalcitonin may be associated with reduced antibiotic usage compared to usual care. However, individual randomized controlled trials testing this hypothesis were too small to rule out harm, and the full cost-benefit of this strategy has not been evaluated. The purpose of this analysis was to evaluate the effect of a procalcitonin-guided antibiotic strategy on clinical and economic outcomes.The use of procalcitonin-guided antibiotic therapy.We searched computerized databases, reference lists of pertinent articles, and personal files. We included randomized controlled trials conducted in the intensive care unit that compared a procalcitonin-guided strategy to usual care and reported on antibiotic utilization and clinically important outcomes. Results were qualitatively and quantitatively summarized. On the basis of no effect in hospital mortality or hospital length of stay, a cost or cost-minimization analysis was conducted using the costs of procalcitonin testing and antibiotic acquisition and administration. Costs were determined from the literature and are reported in 2009 Canadian dollars. Five articles met the inclusion criteria. Procalcitonin-guided strategies were associated with a significant reduction in antibiotic use (weighted mean difference −2.14 days, 95% confidence interval −2.51 to −1.78, p < .00001). No effect was seen of a procalcitonin-guided strategy on hospital mortality (risk ratio 1.06, 95% confidence interval 0.86–1.30, p = .59; risk difference 0.01, 95% confidence interval −0.04 to +0.07, p = .61) and intensive care unit and hospital lengths of stay. The cost model revealed that, for the base case scenario (daily price of procalcitonin Can$49.42, 6 days of procalcitonin measurement, and 2-day difference in antibiotic treatment between procalcitonin-guided therapy and usual care), the point at which the cost of testing equals the cost of antibiotics saved is when daily antibiotics cost Can$148.26 (ranging between Can$59.30 and Can$296.52 on the basis of different assumptions in sensitivity analyses).Procalcitonin-guided antibiotic therapy is associated with a reduction in antibiotic usage that, under certain assumptions, may reduce overall costs of care. However, the overall estimate cannot rule out a 7% increase in hospital mortality.