Background: An influence of various psychological factors (e.g., stress or vaccine hesitancy) on antibody response following vaccinations (vac; e.g. influenza, diphteria) has previously been reported. However, these are the first data on vaccine hesitancy’s impact on SARS-CoV-2 vac in a cohort of cancer patients (pts). Methods: Cancer pts at our university oncology center were prospectively enrolled between 01/2021-02/2022. Medical data and blood samples were collected at time of enrollment and before and after every SARS-CoV-2 vac, at 3 and 6 months. Anti-SARS-CoV-2 IgG levels and neutralizing antibodies (nAb) were determined. Pts also completed a questionnaire containing eleven-level Likert items ranging from 1 (“totally disagree”) to 11 (“totally agree”) regarding their attitude towards COVID-19 and vac in general. Results: Samples and questionnaires from 148 pts (41% female) were collected. Mean age was 64 (24-87) years. Most patients suffered from solid tumors (85%), mainly gastrointestinal (GI) cancer (59%), and were on active therapy (92%), mainly chemotherapy (80%). Agreement with “I am against vac in general” was significantly correlated with decreased SARS-CoV-2 IgG titers following first vac (ρ = -0.411, p = 0.018), second vac (ρ = -0.399, p = 0.044) and at 3 months follow-up (ρ = -0.293, p = 0.007) as well as reduced nAb after second vac (ρ = -0.533, p = 0.005) and 3 months (ρ = -0.221, p = 0.043). In contrast, stating “I will definitely get vaccinated against COVID-19” was strongly correlated with increased IgG titers following second vac (ρ = 0.44, p = 0.025). Also, “everyday stress will keep me from getting vaccinated” was significantly associated with decreased IgG and nAb following second vac (ρ = -0.433, p = 0.027; ρ = -0.391, p = 0.048). Multivariate linear regression (MLR) revealed being “against vac in general” as an independent negative predictor of IgG levels after first SARS-CoV-2 vac (β = -0.437, p = 0.022) and at 3 months follow-up (β = -0.292, p = 0.007). Among pts with GI cancer, agreement with “being afraid of vac side effects (SE)” demonstrated significantly decreased IgG (ρ = -0.334, p = 0.025) and nAb titers (ρ = -0.424, p = 0.004) after 3 months. MLR indicated fear of vac SE as an independent negative predictor of nAb after 3 months in this subgroup (β = -0.355, p = 0.025). Additionally, fear of SE was negatively correlated with anti-SARS-CoV-2 antibodies after second vac (ρ = -0.515, p = 0.029) and 3 months in male (ρ = -0.368, p = 0.011), but not in female pts. However, agreement with “I am completely confident that the vac are safe” was only correlated with increased IgG titers at 3 months follow-up in women (ρ = -0.361, p = 0.031). Conclusions: The current study revealed vaccine hesitancy’s significant negative impact on immune response following SARS-CoV-2 vac in cancer pts. Increased efforts to fight vaccine hesitancy are necessary to not only enhance vac coverage but also immune response among cancer pts.