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Canine parvovirus type 2 (CPV-2) infection is reported in vaccinated puppies in Egypt, yet contributing factors remain poorly investigated. This study evaluated the role of vaccination practices and CPV-2 antigenic variation in disease occurrence in puppies whose primary vaccination series was recorded as finished by attending veterinarians. Puppies with clinical signs of parvoviral enteritis at three veterinary clinics in Giza, Egypt (June–October 2020) were enrolled if vaccination history was documented. All non-vaccinated puppies were included, whereas among vaccinated puppies, only those with a stamped finished primary vaccination series regardless of whether international guidelines had been followed were included. Rectal swabs were collected for PCR and VP2 gene sequencing. For vaccinated puppies, associations between PCR positivity and different aspects of vaccination practices, including age at finishing the vaccination series, number of doses, and vaccinal strain, were assessed. The finishing age was categorized as recommended (the final dose was given at ≥ 16 weeks of age, according to international guidelines) or early (< 16 weeks of age). CPV-2 variant distribution among vaccinated and non-vaccinated puppies was also evaluated. Fifty-eight puppies met the inclusion criteria (41 vaccinated, 17 non-vaccinated). CPV-2 was PCR-positive in 28/41 vaccinated and 13/17 non-vaccinated puppies. Early finishing of the primary vaccination series was significantly associated with CPV-2 infection (P < 0.001), whereas vaccinal strain and number of doses were not. Disease developed within one month of vaccination, including six puppies within one week. Sequencing identified 35 new CPV-2a, 3 CPV-2b, and 3 CPV-2c variants, with no significant difference in variant distribution between vaccinated and non-vaccinated puppies (P = 0.16). Finishing the primary vaccination series at ≥ 16 weeks of age, in accordance with international guidelines, is critical to overcome maternally derived antibody interference. Antigenic variation appears to play a minor role in disease occurrence in this setting. CPV-2 Infection after the perceived finishing of vaccination highlights a safety gap, where the veterinary stamp occurs before the 16-week threshold required for effective protection.