In recent years, there has been a marked increase in the diagnostic workups for celiac disease among military personnel, thereby significantly increasing overall laboratory testing expenditures and burden. We evaluated the serologic testing procedure in symptomatic young adults, using a “cost–effect” approach. We evaluated the serologic screening policy for celiac disease among serologically tested military personnel. The study population was divided into subgroups according to the clinical presentation prior to screening: isolated (low-risk) and combined complaints (high-risk). Sensitivity, specificity, and predictive values of serologic markers for celiac disease were evaluated. Cost analyses were based on diagnostic expenditures. Cost–effect ratio is expressed as cost per newly diagnosed patients, and cost minimization as cost per screened individuals. Five hundred thirty-eight military personnel were serologically tested for celiac disease. Eight new cases of celiac were diagnosed, all of whom belonged to the high-risk subgroup and tested positive for at least two positive serologic tests (tTG + EMA or tTG + AGA IgG + EMA). EMA Ab measured the highest sensitivity, specificity, and predictive values. Average screening expenditure was U.S. $287 per patient. The lowest cost–effect and cost minimization ratios were achieved by implementing a two-step single-marker screening protocol for high-risk subjects and one-step follow-up for low-risk subjects. Among patient population of young adults, selective diagnostic workup could result in cost-minimization without risking quality of diagnosis. From a cost–effect perspective, implemented screening procedures need to be dependent on subgroup: low-risk, clinical follow-up; and high-risk, serological testing for EMA and, only if positive, possibly a small-bowel biopsy.