Vaccinations are instances of Human Enhancement (HE) because, as biotechnologies, they are capable of augmenting the human body’s capacities. We hypothesized that vaccination refusal, as observed during the COVID-19 pandemic, indicates a belief system that also determines attitudes toward HE. Rejection of both may be linked to well-known motives: invasiveness and alleged unnaturalness. We tested the relationship between these two phenomena by conducting two online surveys (N = 314 and N = 300; 81.5%/85.7% vaccinated against SARS-CoV-2 and 18.5%/14.33% not). We also examined if getting enhanced (vaccinated) can induce a relational change toward the environment. Study 1 suggested that greater willingness to use methods to enhance cognitive abilities was more likely when methods must be infrequently used and were deemed natural and non-invasive. An affirmative attitude toward naturalness correlated negatively with the willingness to use. Interaction effects suggested increased importance of naturalness and invasiveness associated variables for unvaccinated participants. Interacting with vaccination status, affirmative attitudes toward naturalness were negatively associated with attitudes toward vaccinations and HE. Qualifying vaccination as HE did not reliably predict attitude toward vaccination or HE. Getting vaccinated led to psychological relief. We explored predictors of vaccination intention. Study 2 showed that unvaccinated perceived the vaccine as less natural but as invasive as vaccinated participants. Perceived naturalness and invasiveness were decisive for vaccination refusal. Findings suggest that rejecting vaccination against SARS-CoV-2 may indicate motives associated with rejecting other HE means and may be a valuable behavioral sample to assess a person’s broader belief system.