The treatment of psoriasis in patients with a personal history of cancer is a matter of debate and limited evidence is available to guide clinicians. To report a multicenter real-life experience of a group of patients with psoriasis undergoing treatment with guselkumab and a history of cancer. We conducted a multicenter retrospective Spanish study enrolling patients with moderate-to-severe plaque psoriasis and neoplasia being treated with guselkumab for their psoriasis. Twenty patients with moderate-to-severe psoriasis and at least 12 weeks of ongoing treatment were included. For the analysis, a 52 week follow-up period was evaluated in terms of efficacy and safety. Most of the malignancies in these patients were solid tumors. The percentage of patients achieving psoriasis area and severity index ≤3 at week 12 and week 52 was 80% and 87.5%, respectively, whereas 68.8% of patients achieved psoriasis area and severity index ≤1. A 52-week survival rate of 100% in the study population was observed (n = 20), including those patients with concomitant active cancers (n = 14). No adverse effects or dropouts related to guselkumab safety profile were detected. Guselkumab not only demonstrates high efficacy in treating psoriasis but also exhibits a favorable safety profile in patients with neoplasms.