(1) Background: Psoriasis is a common chronic inflammatory skin disease with different manifestations, affecting the quality of life at social, emotional, and professional dimensions and requiring long-term treatment. This study aimed to investigate the effect of psychosocial and clinical factors on adherence to topical treatment in psoriasis. (2) Methods: Self-reported measures and weighing the medicines were used to assess adherence. Psychopathological symptoms were measured using the Brief Symptoms Inventory (BSI). Social and clinical factors were assessed by a sociodemographic and clinical questionnaire. Adherence to treatment with topical medication was assessed using a sample of 102 psoriasis patients. (3) Results: The explanatory models of adherence to topical treatment in psoriasis translated into positive associations between adherence and the education level (higher education) (p = 0.03; φ = 0.23), the single-family household (p = 0.01; φ = 0.44), active employment status (p = 0.05; φ = −0.19), familiar history of psoriasis (p = 0.04; φ = −0.21), and the presence of obsessive-compulsive symptoms (p = 0.01; d = 0.29). (4) Conclusions: In patients who present the characteristics identified that influence non-adherence, instructions should be reinforced to increase adherence. The experimental mortality (39.6%) reduced the sample size, representing a limitation of the study.