Background - In France, approximately 40,000 people are unaware that they are infected with HIV. Although previous studies have assessed the cost-effectiveness of routine HIV testing in the United States, differences in the epidemiological situation and attitudes toward HIV testing warranted a specific analysis for France. Methods and Key Results - We assessed the life expectancy, cost, and cost-effectiveness of alternative HIV testing strategies in France among the general population and at-risk populations, using a mathematical model informed by French clinical and cost data. We compared the "current" screening strategy, targeting populations at risk of HIV infection, with a "universal screening" strategy, in which voluntary HIV testing is offered to all adults aged 18 to 69. The frequency of testing ranged from a one-time test to an annual test. The data used in the model included the average age (42 years), the prevalence of undiagnosed HIV infections (0.10%), the annual incidence of HIV (0.01%), test acceptance (79%), referral to healthcare facilities (75%), and the cost of testing (43 euros). We performed sensitivity analyses on the prevalence of undiagnosed infections, HIV incidence, and cost estimates, and we analyzed the benefits of antiretroviral treatment on transmission. For the "current strategy," we obtained a life expectancy of 242.82 quality-adjusted life months (QALM) among people living with HIV and 268.77 QALM in the general population. Conducting a one-time screening test offered to the entire population increased life expectancy by 0.01 QALM in the general population and increased costs by 50 euros per person, resulting in a cost-effectiveness ratio of 57,400 euros per quality-adjusted life year (QALY). More frequent screening in the general population increased survival, costs, and cost-effectiveness ratios. For people who inject drugs (prevalence of undiagnosed cases 6.17%; HIV incidence 0.17%/year) and the population of French Guiana (prevalence 0.41%; incidence 0.35%/year), annual screening was associated with cost-effectiveness ratios of 51,200 euros and 46,500 euros/QALY, compared to screening every five years. Conclusions - This modeling suggests that offering a one-time screening test to the entire population in France improves survival compared to the "current strategy" and is associated with a cost-effectiveness ratio comparable to other screening interventions recommended in Western Europe. In at-risk groups, more frequent screening is justified from an economic standpoint. (R.A.)