ABSTRACT: BACKGROUND:The content of online computer-tailored interventions is often determined to match an individual's characteristics, beliefs, and behavioral factors. These content-tailored interventions lead to better message processing and a higher likelihood of behavior change such as smoking cessation. However, a meta-analysis of online computer-tailored interventions showed that effect sizes, albeit positive, remain small, suggesting room for improvement. A promising strategy to enhance the effectiveness of online computer-tailored interventions is to tailor the message frame (ie, how a message is communicated) based on the preferred communication style of the user in addition to content-tailoring. One factor that determines an individual's communication style preference is the need for autonomy; some individuals prefer an autonomy-supportive communication style (offering choice and use of suggestive language), whereas others might prefer a directive communication style, which is replete with imperatives and does not provide choice. Tailoring how messages are presented (eg, based on the need for autonomy) is called message frame-tailoring. OBJECTIVE:The aim of the present study was to test the effectiveness of message frame-tailoring based on the need for autonomy, in isolation and in combination with content-tailoring, within the context of an online computer-tailored smoking cessation intervention. The primary outcome measure was the 7-day point-prevalence of smoking abstinence. Secondary outcomes were perceived message relevance, self-determined motivation to quit smoking, and sociocognitive beliefs. METHODS:A randomized controlled trial with a 2 (message frame-tailoring vs no message frame-tailoring) by 2 (content-tailoring vs no content-tailoring) design was conducted among adult smokers intending to quit smoking (N=273). RESULTS:Structural equation modeling revealed that the content-tailored condition increased smoking abstinence rates 1 month after the start of the intervention (beta=.57, P=.02). However, neither message frame-tailoring nor its interaction with content-tailoring significantly predicted smoking abstinence. In our model, message frame-tailoring, content-tailoring, as well as their interaction significantly predicted perceived relevance of the smoking cessation messages, which consequently predicted self-determined motivation. In turn, self-determined motivation positively affected attitudes and self-efficacy for smoking cessation, but only self-efficacy consequently predicted smoking abstinence. Participants in the control condition perceived the highest level of message relevance (mean 4.78, SD 1.27). However, messages that were frame-tailored for individuals with a high need for autonomy in combination with content-tailored messages led to significantly higher levels of perceived message relevance (mean 4.83, SD 1.03) compared to those receiving content-tailored messages only (mean 4.24, SD 1.05, P=.003). CONCLUSIONS:Message frame-tailoring based on the need for autonomy seems to be an effective addition to conventional content-tailoring techniques in online smoking cessation interventions for people with a high need for autonomy; however, this is not effective in its current form for people with a low need for autonomy. TRIAL REGISTRATION:Dutch Trial Register (NL6512/NRT-6700); https://www.trialregister.nl/trial/6512.