In population-wide cancer screening, three key issues need to be focused on: number of cancer cases identified, number of false positives, and cost. OncoSeek is a multi-cancer early detection (MCED) test using seven protein tumor markers (PTMs) and artificial intelligence (AI). SeekInCare is an MCED test that integrates the seven PTMs and four cancer genomic features from cell-free DNA by shallow whole-genome sequencing. In a two-step approach, the initial screening is conducted using OncoSeek, and SeekInCare is then used as the secondary test for those individuals who tested positive by OncoSeek. We simulated a screening in five million adults aged ≥ 50 years with a cancer incidence rate of 1.9%. While at 91.0% specificity OncoSeek had 441,450 false positives, using the two-step approach significantly reduced false positives to 34,335 (0.7%). Although SeekInCare and Galleri identified more cancer cases (32,015 and 27,455, respectively) than the two-step MCED (21,280), their total costs reached $3,750 million and $4,745 million respectively. As the positive predictive value (PPV) of two-step (38.3%) was comparable to SeekInCare (27.7%) and Galleri (38.3%), it reduced cost 5.3-fold and 6.6-fold, respectively, amounting to a total cost of $713.6 million and a cost of $143 per individual screened. The cost of per cancer case detected was $117,133 for SeekInCare and $172,828 for Galleri, which were 3.5-fold and 5.2-fold higher, respectively, than the two-step MCED ($33,534). The two-step approach not only significantly reduces false positives, but also cuts the screening cost down substantially, making it a cost-effective strategy for population-wide cancer screening.