Keratinocyte cancer (KC) is the most common form of cancer in humans. To our knowledge, no previous publications assessing the methodological quality of clinical trials for the prevention of KC have been recently published. We aim to assess the methodological quality of clinical trials focused on the prevention of KC in high-risk groups not receiving immunosuppressive therapy (NRIT) and propose solutions to improve the design of future trials. We searched clinical trials in which the main outcome was the prevention of KC in high-risk NRIT groups using the strategy published in the International Prospective Register of Systematic Reviews (PROSPERO registry), CRD42016045981. Consolidated Standards of Reporting Trials (CONSORT) criteria and the Cochrane Collaboration risk of bias tool were used to assess methodological quality. We analyzed 23 clinical trials. We found a high risk of attrition and reporting bias in 86.9% and 60.9% of the trials, respectively. Regarding the CONSORT criteria, in at least 40% of the trials, the authors omitted the following information: a description of the trial design, the number of losses and exclusions after randomization, the results of subgroup and adjusted analysis, the estimated effect size and the precision of primary and secondary outcomes. Methodological quality was improved in the recently published clinical trials compared to those published before the CONSORT criteria development. All clinical trials should report in detail the information used to assess potential risks of bias.