Studies have indicated that individuals with compromised immune systems display substantially weaker antibody reactions to COVID-19 vaccines. Patients suffering from solid malignancies exhibit decreased immunogenicity following COVID-19 vaccination or infection. The current investigation examined antibody reactions to COVID-19 infection and/or the Pfizer-BioNTech BNT162b2 mRNA vaccine in individuals with cancer undergoing active therapy. Additionally, prior publications were surveyed to pinpoint patient subgroups potentially benefiting from an additional vaccine dose. Levels of anti-SARS-CoV-2 S1/S2 IgG antibodies were determined in a group of 202 patients with cancer actively treated with chemotherapy (96 cases), immunotherapy (52), targeted biologic agents (46), or endocrine therapy (12) for either localized (n = 66, 32.7%) or advanced (n = 136, 67.3%) malignancy. Of these participants, 172 completed a two-dose vaccination series, whereas 30 experienced natural COVID-19 infection (including 20 who also received a single vaccine dose). For cases yielding borderline anti-S1/S2 findings, anti-receptor-binding domain antibodies were assayed separately. Seropositivity for SARS-CoV-2 antibodies reached 89.1% (180/202) in cancer patients after either vaccination or infection, and 87.2% (150/172) in vaccinated individuals without prior infection—significantly lower than the 100% rate observed in 30 healthy healthcare workers (P < 0.001). Chemotherapy emerged as an independent predictor of impaired antibody production after infection or vaccination, yielding an 81.3% positivity rate compared to 96.2% among those on alternative therapies (P = 0.001). In chemotherapy recipients who were vaccinated, seropositivity stood at 77.5%. Multivariable regression revealed higher likelihood of robust neutralizing titers (>60 AU/ml) with immunotherapy (odds ratio 2.44) and lower likelihood with chemotherapy (odds ratio 0.39). Taken together, both the BNT162b2 vaccine and prior SARS-CoV-2 infection provoke substantial antibody production in most cancer patients. Nonetheless, this work pinpoints individuals on chemotherapy as exhibiting markedly impaired seroconversion and reduced titer magnitudes. Such evidence advocates for intensified viral and antibody monitoring in this population, alongside preferential allocation of booster vaccinations, especially amid the rise of more transmissible viral strains.