Vulvar cancer (VC) can be subclassified by human papillomavirus (HPV) status. HPV-negative VCs frequently harbor mutations; however, in-depth analysis of other potential molecular genetic alterations is lacking. We comprehensively assessed somatic mutations in a large series of vulvar (pre)cancers. We performed targeted next-generation sequencing (17 genes), p53 immunohistochemistry and HPV testing on 36 VC and 82 precursors (sequencing cohort). Subsequently, the prognostic significance of the three subtypes identified in the sequencing cohort was assessed in a series of 236 VC patients (follow-up cohort). Frequent recurrent mutations were identified in HPV-negative vulvar (pre)cancers in (42% and 68%), (28% and 41%), and (20% and 31%). Mutation frequency in HPV-positive vulvar (pre)cancers was significantly lower ( = 0.001). Furthermore, a substantial subset of the HPV-negative precursors (35/60, 58.3%) and VC (10/29, 34.5%) were wild-type (wt), suggesting a third, not-previously described, molecular subtype. Clinical outcomes in the three different subtypes (HPV , HPV /p53wt, HPV /p53abn) were evaluated in a follow-up cohort consisting of 236 VC patients. Local recurrence rate was 5.3% for HPV , 16.3% for HPV /p53wt and 22.6% for HPV /p53abn tumors ( = 0.044). HPV positivity remained an independent prognostic factor for favorable outcome in the multivariable analysis ( = 0.020). HPV and HPV vulvar (pre)cancers display striking differences in somatic mutation patterns. HPV /p53wt VC appear to be a distinct clinicopathologic subgroup with frequent mutations. HPV VC have a significantly lower local recurrence rate, independent of clinicopathological variables, opening opportunities for reducing overtreatment in VC. .