BACKGROUND: Large-scale PCR-based SARS-CoV-2 testing is expensive, resource-intensive, and time-consuming. A self-collection approach is a probable alternative; however, it requires evaluating the feasibility, expenses, and the ability to prevent infections. OBJECTIVE: This study aims to compare an innovative self-collection approach with a regular SARS-CoV-2 testing strategy in a large European industrial manufacturing site. METHODS: The feasibility of a telemedical PCR-based self-collection approach was assessed for 150 employees (intervention group) and compared with a regular SARS-CoV-2 testing approach (n=143, control group). Acceptance, ergonomics, and efficacy were evaluated using a software application. A simulation model was implemented to evaluate the effectiveness. An interactive R shiny app was created to enable customized simulations. RESULTS: The test results were successfully communicated and interpreted without uncertainty by 76% and 77% of the participants in the intervention and control groups, respectively (P=.96). The ratings for the acceptability, ergonomics, and efficacy of the intervention group were noninferior when compared with those of the control group (acceptability: 71.6% versus 37.6%; ergonomics: 88.1% versus 74.5%; efficacy: 86.4% versus 77.5%). The self-collection approach was found to be less time consuming (23 min versus 38 min, P<0.001). The simulation model indicated that both testing approaches reduce the risk of infection and the self-collection approach tends to be slightly less effective owing to the lower sensitivity. CONCLUSIONS: The self-collection approach for SARS-CoV-2 diagnosis is technically feasible and is well rated in terms of acceptance, ergonomics, and efficacy. The simulation model facilitates the evaluation of the test effectiveness; nonetheless, considering the context specificity, appropriate adaption by the companies is required.