The presence of IgA- and IgM-specific autoantibody (AAb) isotypes and their relationship to p53 tissue expression patterns are not well understood. This study aims to investigate the clinical utility of the anti-p53 AAb isotypes and tissue positivity in colorectal cancer (CRC). We analyzed anti-p53 IgG, IgM, and IgA AAbs in sera of 99 CRC patients and 99 non-cancer control subjects. Corresponding tissue expression of the p53 protein was evaluated by immunohistochemistry (IHC). Anti-p53 AAbs of the IgG isotype were present in the sera of 21 out of 99 patients (21%), whereas IgM AAbs were observed in 9 (9%) and IgA in 2 (2%) CRC patients. Anti-p53 AAbs of all 3 isotypes were generally associated with IHC staining indicative of mutated TP53. Seropositive anti-p53 IgM cases in the absence of anti-p53 IgG were linked to wild-type p53. Anti-p53 IgA in the absence of IgG AAbs was detected in 2 non-cancer controls indicating a potential p53 epitope mimicry. Although seropositivity was not associated with patient survival (P = .650), mutant-pattern p53 tissue expression was associated with reduced 5-year overall survival (P = .032); however, it was not an independent prognostic marker (multivariate Cox regression, P = .193). In conclusion, immunoglobulin isotyping revealed that anti-p53 IgM and IgA AAbs were predominantly concurrent with anti-p53 serum IgG and the mutant-pattern p53 tissue phenotype. IgM and IgA seropositive cases in absence of anti-p53 IgG were linked to wild-type p53 tissue phenotype indicating early anti-p53 immune responses preceding isotype class-switch (IgM) or p53 antigen mimicry (IgA).