Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition. Display omitted •Germline, gain-of-function NLRP1 mutations cause MSPC and FKLC syndromes.•Mutant NLRP1 proteins have lower threshold for inflammasome activation.•The Pyrin (PYD) and LRR domains of NLRP1 inhibit its self-oligomerization.•NLRP1 mutants cause skin hyperplasia via paracrine inflammatory signaling. Gain-of-function mutations in the inflammasome sensor NLRP1 increase susceptibility to skin cancer and unmask unique regulatory autoinhibition in the inflammasome.