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Psoriasis can involve the skin, joints, nails and cardiovascular system and result in a significant impairment in quality of life. Studies have shown a lower response rate to systemic anti-psoriatic therapies in smokers, and smoking is a trigger factor for psoriasis. The aim of this study was therefore to analyse the response to systemic therapies for psoriasis, with a focus on smoking. Prospectively collected data from patients with moderate to severe psoriasis included in the national psoriasis registries for Germany and Switzerland (PsoBest and SDNTT) were analysed. Therapy response was defined as reaching a Psoriasis Area and Severity Index (PASI) reduction of 75%, PASI ≤ 3 or Dermatology Life Quality Index (DLQI) ≤ 1. Out of 5,346 patients included in these registries, 1,264 met the inclusion criteria for this study. In the smoking group, 715 (60.6%) reached therapy response at month 3, compared with 358 (63.7%) in the non-smoking group (p ≤ 0.269), 659 (74.1%) vs. 330 (77%) reached therapy response at month 6 (p ≤ 0.097), and 504 (76.6%) vs. 272 (79.0%) at month 12 (p ≤ 0.611). Therefore, these data do not show that smoking affects the response rate of anti-psoriatic therapy after 3, 6 and 12 months.