OBJECTIVES Nonalcoholic fatty liver disease (NAFLD) is the most common liver condition in Western countries. To date, no studies have examined the cost-effectiveness of screening for nonalcoholic steatohepatitis (NASH), its advanced form.  METHODS We performed a cost-utility analysis of annual non-invasive screening strategies using a third-party payer perspective in a general population and compared it to screening in a high-risk obese or diabetic population. Screening algorithms involved well-studied non-invasive techniques including NAFLD fibrosis score, ultrasound transient elastography (TE), and ultrasound acoustic radiation force impulse (ARFI) imaging for detecting advanced fibrosis (≥ F3); and plasma cytokeratin-18 for NASH detection. Liver biopsy and magnetic resonance elastography (MRE) were compared as confirmation methods. Model uncertainties were tested using sensitivity analyses. Canadian dollar costs were adjusted for inflation and discounted at 5%. Incremental cost-effectiveness ratio (ICER) of $C50,000 per quality-adjusted life year (QALY) or less was considered cost-effective.  RESULTS Compared with no screening, screening with NAFLD fibrosis score/TE/CK-18 algorithm with MRE as confirmation for advanced fibrosis had an ICER of $C26,143 per QALY gained. Screening in high-risk obese or diabetic populations was more cost-effective, with an ICER of $C9,051 and $C7,991 per QALY gained respectively. Screening algorithms with liver biopsy confirmation were not found to be cost-effective. Sensitivity analyses revealed that the screening starting age, the annual transition probability from simple steatosis to NASH, and the cost of a TE exam had the most impact on the results.  CONCLUSIONS Our model suggests that annual NASH screening in high-risk obese or diabetic populations can be cost-effective.