Background: Clinical practice guidelines are evidence-based recommendations used by physicians to improve patient care. These guidelines provide the physician with an assessment of the benefits and harms of a treatment and its alternatives. Therefore, it is essential that the clinical practice guidelines be based on the strongest available evidence. Numerous studies in a variety of different fields of medicine have demonstrated that recommendations supported by weak evidence are a common theme in clinical practice guidelines. A clinical guideline based solely on weak evidence has the capability to reduce the quality of care provided by physicians. Objective: Our primary objective is to evaluate the levels of evidence supporting the recommendations constituting the American Academy of Dermatology clinical practice guidelines. Methods: Using a cross-sectional study design, authors SM and RO located all current clinical practice guidelines on the American Academy of Dermatology website on June 10, 2017, and December 11, 2019. Each recommendation and its corresponding evidence rating were extracted in a duplicate and blinded fashion. A consensus meeting was planned a priori to resolve disagreements in extractions or stratifications. Results: In total, 6 clinical guidelines and their subsections were screened and 899 recommendations were identified. Our final data set included 841 recommendations, as 58 recommendations contained no level of evidence and were excluded from calculations. Many recommendations were supported by a moderate level of evidence and therefore received a B rating (346/841, 41.1%). Roughly one-third of the recommendations were supported by a strong level of evidence and were given an A rating (n=307, 36.5%). The clinical practice guideline with the highest overall strength of evidence was regarding the treatment of acne, which had 17 of 35 (48.6%) recommendations supported by strong evidence and only 2 (5.7%) supported by weak evidence. The clinical practice guideline with the fewest recommendations supported by strong evidence was melanoma (13/63, 20.6%). Conclusions: Clinical practice guidelines that lack strong supporting evidence could negatively affect patient care, and dermatologists should be mindful that not all recommendations are supported by the strongest level of evidence. An increased quantity of quality research needs to be performed in the field of dermatology to improve the evidence supporting the American Academy of Dermatology clinical practice guidelines. [JMIR Dermatol 2020;3(1):e17370]