ABSTRACT: To develop a spore inactivation strategy, the effect of 15-min hydrostatic pressure treatments (550 and 650 MPa) at 55 and 75 °C in citric acid buffer (4.75 and 6.5 pH) on spores of 5 isolates of Clostridium perfringens type A carrying the gene that encodes the C. perfringens enterotoxin (cpe) on the chromosome (C-cpe), 4 isolates carrying the cpe gene on a plasmid (P-cpe), and 2 strains of C. sporogenes were investigated. Treatments at 650 MPa, 75 °C and pH 6.5 were moderately effective against spores of P-cpe (approximately 3.7 decimal reduction, DR) and C. sporogenes (approximately 2.1 DR) but not for C-cpe (approximately 1.0 DR) spores. Treatments at pH 4.75 were moderately effective against spores of P-cpe (approximately 3.2 DR) and C. sporogenes (approximately 2.5 DR) but not of C-cpe (approximately 1.2 DR) when combined with 550 MPa at 75 °C. However, when pressure was raised to 650 MPa under the same conditions, high inactivation of P-cpe (approximately 5.1 DR) and C. sporogenes (approximately 5.8 DR) spores and moderate inactivation of C-cpe (approximately 2.8 DR) spores were observed. Further advances in high-pressure treatment strategies to inactivate spores of cpe-positive C. perfringens type A and C. sporogenes more efficiently are needed.