Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Delta variant breakthrough infections in nursing home residents following vaccination with Comirnaty® COVID‐19 vaccine were characterized. In total, 201 participants (median age, 87 years; range, 64–100; 133 female) from two nursing homes in the Valencian community (Spain) were included. SARS‐CoV‐2‐Spike (S) antibody responses were determined by a lateral flow immunocromatography (LFIC) assay and by quantitative electrochemiluminescent assay in LFIC‐negative participants. SARS‐CoV‐2‐S‐IFNγ T cells were enumerated by flow cytometry in 10 participants. Nasopharyngeal SARS‐CoV‐2 RNA loads were quantified by real‐time polymerase chain reaction assays. Vaccine breakthrough COVID‐19 due to the Delta variant occurred in 39 residents (median age, 87 years; range, 69–96; 31 female) at a median of 6.5 months after vaccination (nine requiring hospitalization). Breakthrough infections occurred at a higher rate (p < 0.0001) in residents who had not been previously infected with SARS‐CoV‐2 (naïve) (33/108; 18%) than in those with prior diagnosis of SARS‐CoV‐2 infection (experienced) (6/93; 6.4%), and were more likely ( p < 0.0001) to develop in residents who tested negative by LFIC (20/49) at 3 months after vaccination as compared to their LFIC‐positive counterparts (19/142). Among LFIC‐negative residents, a trend towards lower plasma anti‐RBD antibody levels was noticed in those developing breakthrough infection ( p = 0.16). SARS‐CoV‐2 RNA loads in nasopharyngeal specimens were lower in SARS‐CoV‐2‐experienced residents ( p < 0.001) and in those testing positive by LFIC ( p = 0.13). The frequency of SARS‐CoV‐2‐S‐reactive T cells at 3 months was similar in LFIC‐negative residents with ( n = 7) or without ( n = 3) breakthrough infection. Prior history of SARS‐CoV‐2 infection and detection of S‐reactive antibodies by LFIC at 3 months is associated with a lower risk of Delta‐variant breakthrough infection in nursing home residents at midterm after Comirnaty® COVID‐19 vaccination.