OBJECTIVES: To develop a cost-minimizing protocol to reduce the administration of unnecessary immunizations through the use of serologic screening to antibodies against selected diseases for which enlisted accessions to the US Army currently receive universal immunization. METHODS: A detailed decision tree containing over 180,000 terminal nodes was constructed using TreeAge software to model the variable costs of serologic screening and immunization series delivery among four policy options: 1) current policy, involving selective varicella serology based on history; 2) universal hepatitis B serology with selective varicella serology; 3) universal serology for hepatitis B, varicella, measles and rubella; and 4) universal serology for hepatitis A and B, varicella, measles and rubella. Parameters for the model included levels of pre-existing immunity to each disease, rates of attrition between vaccine doses, current vaccine and serologic screening costs, and test sensitivity and specificity. Outcome measures included total variable costs per accession, and probability of missed immunization due to false positive test results. Due to the complexity of the tree, expected values were calculated via 10,000 runs of microsimulation repeated 1,000 times to construct confidence intervals. RESULTS: All policy options with universal serologic screening demonstrated significant variable cost savings over current policy. Policy option three minimized costs, with savings of $22.71 per accession (95% CI $22.68-$22.74). Cost savings were qualitatively robust to probabilistic sensitivity analysis. Numbers of missed immunizations due to false positive test results were comparable between current and proposed policies, with policy option three resulting in only 244 additional missed immunizations per 100,000 accessions (95% CI 233-256) relative to current policy. CONCLUSIONS: Due to high levels of pre-existing immunity, enlisted accessions to the US Army currently receive multiple unnecessary immunizations. Universal serologic screening to hepatitis B, measles, rubella, and varicella provides significant variable cost savings without a clinically significant increase in disease susceptibility.