Background: Improving questionnaire response rates is an everlasting issue for research. Today, the Internet can easily be used to collect data quickly. However, collecting data on the Internet can lead to biased samples because not everyone is able to access or use the Internet. The older population, for example, is much less likely to use the Internet. The Patient-Reported Outcomes Following Initial Treatment and Long-Term Evaluation of Survivorship (PROFILES) registry offers a platform to collect Web-based and paper questionnaires and to try different measures to improve response rates. Objective: In this study, our aim was to study the influence of two methods of invitation on the response rate. Our second aim was to examine the preference of questionnaire mode of administration (paper or Web-based) for the older patient in particular. Methods: To test these two invitational methods, 3406 colorectal cancer patients between ages 18 and 85 years received an invitation containing an access code for the Web-based questionnaire. They could also request a paper questionnaire with an included reply card (paper-optional group). In contrast, 179 randomly selected colorectal cancer patients received a paper questionnaire with the invitation (paper-included group). They could also choose to fill out the Web-based questionnaire with the included access code. Results: Response rates did not differ between the paper-optional and the paper-included groups (73.14%, 2491/3406 and 74.9%, 134/179, P=.57). In the paper-optional group, online response was significantly higher when compared to the paper-included group (41.23%, 1027/2491 vs 12.7%, 17/134, P<.001). The majority of online respondents responded after the first invitation (95.33%, 979/1027), which was significantly higher than the paper respondents (52.19%, 764/1464, P<.001). Respondents aged 70 years and older chose to fill out a paper questionnaire more often (71.0%, 677/954). In the oldest age group (≥80 years), 18.2% (61/336) of the respondents filled out a Web-based questionnaire. Conclusions: The lack of difference in response rates between invitation modes implies that researchers can leave out a paper questionnaire at invitation without lowering response rates. It may be preferable not to include a paper questionnaire because more respondents then will fill out a Web-based questionnaire, which will lead to faster available data. However, due to respondent preference, it is not likely that paper questionnaires can be left out completely in the near future.