© 2019, © 2019 Taylor & Francis Group, LLC. Incarcerated men in the United States, an understudied population, have not been the focus of cancer prevention research. This pilot study explored the impact of Cancer 101 for imprisoned male smokers to increase cancer knowledge and promote cancer prevention activities in the prison population. Cancer 101 was pilot tested for adoption with representatives from the target audience in three prison facilities located in the northeastern region of the United States, and based on their feedback, modifications were implemented. Pretest and posttest surveys were used to assess knowledge of attitudes regarding the benefits of cancer prevention activities at baseline and immediately after completing Cancer 101. Furthermore, a paired t test procedure was used to determine whether cancer knowledge improved after participating in the Cancer 101 program. A total of 161 men completed all of the modules, participated in pre/post assessments, and qualitatively described their behavioral intentions to participate in activities that could reduce cancer risk. The mean cancer knowledge scores differed before and after completing Cancer 101, t(163) = −14.67, p <.001. Regarding age, the older the respondent, the higher their cancer knowledge score, r =.29, p <.001. This study showed improvements in cancer knowledge scores and behavioral intentions to participate in activities to reduce cancer. Cancer 101 provides opportunities for inmates to increase cancer knowledge, as well as promote action for cancer control during incarceration.