The influence of the vehicle in topical treatment adherence remains to be elucidated. The aim of this study is to analyze the influence of the pharmaceutical dosage form on adherence to topical treatment in psoriasis patients, taking into consideration the mechanical features. The adherence was evaluated in a sample of 102 psoriasis patients, followed for approximately 45 days. Adherence was calculated with a new combined methodology using a log and medication weights. The effect of the group formulation was evaluated using logistic regression models. A complex effect of the vehicle on adherence was found, mediated by the affected area. The adherence was significantly higher for patients applying gels and creams than for those using ointments, whenever the body area affected was extensive. The opposite was found when the affected area was small. Mechanical properties can partially explain the findings since gels and creams may be easier to apply. Patient beliefs and preferences regarding vehicles and their sensory attributes might also explain the results. It is noteworthy that adherence was strikingly low, with more than 75% non-adherent patients. This real-world evidence provides an insight for pharmaceutical industries and guidance for treatment prescription by physicians aiming to address the public health emergency of treatment non-adherence.