Background Internet-delivered cognitive behavioral therapy (ICBT) for alcohol misuse has potential to radically improve access to evidence-based care, and there is a need to investigate ways to optimize its delivery in clinical settings. Guidance from a clinician has previously been shown to improve drinking outcomes in ICBT, and some studies suggest that pre-treatment assessments may contribute in initiating early change. The objective of this study was to investigate the added and combined effects of a pre-treatment assessment interview and guidance on the outcomes of ICBT for alcohol misuse delivered in an online therapy clinic. Methods A 2X2 factorial randomized controlled trial was conducted where participants received access to an 8-week ICBT program, and either a pre-treatment assessment interview (Factor 1), guidance (Factor 2), a combination of these, or neither of these. Participants were 270 individuals (66.8% female, mean age = 46.5) scoring 8 or more on the Alcohol Use Disorders Identification Test and consuming 14 standard drinks or more in the preceding week. Primary outcomes were number of drinks consumed and number of heavy drinking days during the preceding week, 3 months post-treatment. Results Large within-group effects were found in terms of alcohol reductions (dw ≥ 0.82, p < 0.001), but neither of the factors significantly improved drinking outcomes. Guidance was associated with greater adherence (i.e. completed modules). Conclusions Neither a pre-treatment assessment interview nor guidance from a clinician appears to improve drinking outcomes resulting from internet-delivered cognitive behaviour therapy for alcohol misuse when delivered in a routine online therapy clinic. Trial registration: NCT03984786. Registered 13 June 2019, https://clinicaltrials.gov/ct2/show/NCT03984786

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