Introduction. Management of moderate-severe psoriasis is challenging in the presence of severe systemic comorbidities, such as HIV infection, recent history of cancer, latent tuberculosis infection, or advanced liver disease. These patients are almost invariably excluded from randomized clinical trials, an aspect that limits the availability of standardized therapeutic options. Material and methods. This narrative review summarizes the current literature on immunomodulatory therapeutic strategies in patients with psoriasis and severe systemic comorbidities, integrating existing evidence in the literature with relevant clinical observations from real-world practice. Results. Available data suggest that therapeutic decisions should be individualized according to the type of comorbidities and severity of the disease. In well-controlled HIV infection, conservative strategies may be preferred. In patients with a history of cancer, systemic therapies may be used with caution and in interdisciplinary collaboration. In latent tuberculosis infection, prophylaxis is necessary, but isoniazid-induced hepatotoxicity is an important limitation. In liver disease, biological therapies may constitute a safer alternative to conventional systemic therapy. Conclusion. In this context, patients with psoriasis and severe associated systemic comorbidities require a personalized, multidisciplinary approach and close monitoring. Real-world data play an essential role in guiding therapeutic decisions in this patient population.