A growth compromised herpes simplex virus type 2 (HSV-2) mutant which is deleted in the PK domain of the large subunit of ribonucleotide reductase (ICP10ΔPK) protects from fatal HSV-2 challenge in the mouse model (Aurelian L, Kokuba H, Smith CC. Vaccine potential of a Herpes Simplex Virus type 2 mutant deleted in the PK domain of the large subunit of ribonucleotide reductase (ICP10). Vaccine 1999;17:1951–1963). Here we report the results of our studies with ICP10ΔPK in the guinea pig model of recurrent HSV-2 disease. ICP10ΔPK was also compromised for growth and disease causation in this model. It was not isolated from latently infected ganglia by explant co-cultivation. The proportions of latently infected ganglia were significantly lower for ICP10ΔPK than HSV-2 [3/25 (12%) and 7/10 (70%), respectively]. Similar results were obtained for the levels of viral DNA (8×10³ and 2×10⁵ molecules/ganglion for ICP10ΔPK and HSV-2, respectively]. ICP10ΔPK immunization caused a significant (P≤0.001) decrease in the proportion of animals with primary [1/14 (6%) and 16/16 (100%) for ICP10ΔPK and PBS, respectively) and recurrent [1/14 (6%) and 11/14 (79%) for ICP10ΔPK and PBS, respectively) HSV-2 skin lesions. It also protected from genital HSV-2 disease [1/10 and 10/10 for ICP10ΔPK and PBS, respectively] and decreased the severity of the lesions in both models. Quantitative PCR (Q-PCR) with primers that distinguish between HSV-2 and ICP10ΔPK indicated that immunization reduced the proportion of ganglia positive for HSV-2 DNA [8/25 (32%) and 7/10 (70%) for ICP10ΔPK and PBS, respectively) and its levels [3×10³ and 2×10⁵ molecules/ganglion for ICP10ΔPK and PBS, respectively]. The proportion of HSV-2 infected animals with recurrent disease was also significantly (P≤0.001) decreased by immunization with ICP10ΔPK [1/15 (7%) and 11/14 (79%) with recurrent disease for ICP10ΔPK and PBS, respectively], suggesting that ICP10ΔPK has prophylactic and therapeutic activity in the guinea pig.