OBJECTIVES: To compare the cost-effectiveness of an early cancer surveillance strategy versus no surveillance for patients with TP53 germline mutations. METHODS:  A Markov decision analytic model was developed to estimate cost-effectiveness over a lifetime from a US third-party payer perspective. The model consisted of 4 possible health states: no cancer, cancer, post-cancer survivorship, and dead. Model probabilities and costs were populated using estimates from SEER database and published literature. Model outcomes included costs (2015 USD) and effectiveness (life years [LY] gained) of each surveillance strategy and incremental cost-effectiveness ratios (ICERs) comparing surveillance versus no surveillance strategies. Sensitivity analyses examined parameter uncertainty. RESULTS:  The model showed a mean cost of $46,496 and $117,102 and yielded 23 and 27 LY for the non-surveillance and surveillance strategies, respectively. The ICER for early cancer surveillance versus no surveillance was $17,125 per additional LY gained. Sensitivity analyses showed that probability of tumor development and cost of surveillance had the largest impact on model result. At the commonly accepted willingness to pay above $50,000/life-year gained, surveillance had a 94% probability of being the most cost-effective strategy for early cancer detection in this high-risk population. CONCLUSIONS:  Early cancer surveillance is cost-effective for patients with TP53 germline mutations. This is one of the first studies to explore cost-effectiveness of LFS cancer surveillance; the model will continue to improve in accuracy as it is validated with real world data.