Background In 2008, a nationwide skin cancer screening (SCS) program was implemented in Germany. However, participation rates remain low. Objective The overall objective of the HELIOS study is to identify subgroup-specific invitation and communication strategies to increase informed SCS participation in Germany. Methods Focus group discussions will be performed in Erlangen, Germany, to explore potential invitation and communication strategies as well as possible barriers and motivating factors to participate in SCS. Male and female patients of different age groups who have already been diagnosed with skin cancer, as well as participants without a prior diagnosis of skin cancer, will be invited. Based on these results, an online questionnaire will be developed to identify subgroup-specific invitation strategies. A random sample of 2500 persons from the general population aged >35 years from the Munich area will be contacted to complete the questionnaire. Besides descriptive analysis, multinomial logistic regression will be performed. Additionally, a cluster analysis will be conducted to discover patterns or similarities among the participants. Results Recruitment for the focus group studies started in February 2021 and is ongoing. As of August 2021, we have enrolled 39 participants. We expect to end enrollment in the qualitative study in September 2021 and to finish the analysis in December 2021. The second part of the study will then start in January 2022. Conclusions The results of this project will enable us to derive improved and more efficient invitation and communication strategies for SCS. These may be implemented in the future to facilitate increased SCS uptake and early skin cancer detection. International Registered Report Identifier (IRRID) DERR1-10.2196/31860