INTRODUCTION: Human papillomavirus (HPV) vaccination rates are low in young adults. Clinical decision support (CDS) in primary care may increase HPV vaccination. We tested the treatment effect of algorithm-driven, web-based, and electronic health record-linked CDS with or without shared decision-making tools (SDMT) on HPV vaccination rates compared to usual care (UC). METHODS: In a clinic cluster-randomized control trial conducted in a healthcare system serving a largely rural population, we randomized 34 primary care clinic clusters (with three clinics sharing clinicians randomized together) to: CDS; CDS+SDMT; UC. The sample included young adults aged 18-26 due for HPV vaccination with a study index visit from 08/01/2018-03/15/2019 in a study clinic. Generalized linear mixed models tested differences in HPV vaccination status 12 months after index visits by study arm. RESULTS: Among 10,253 patients, 6,876 (65.2%) were due for HPV vaccination, and 5,054 met study eligibility criteria. In adjusted analyses, the HPV vaccination series was completed by 12 months in 2.3% (95% CI: 1.6%-3.2%) of CDS, 1.6% (95% CI: 1.1%-2.3%) of CDS+SDMT, and 2.2% (95% CI: 1.6%-3.0%) of UC patients, and at least one HPV vaccine was received by 12 months in 13.1% (95% CI: 10.6%-16.1%) of CDS, 9.2% (95% CI: 7.3%-11.6%) of CDS+SDMT, and 11.2% (95% CI: 9.1%-13.7%) of UC patients. Differences were not significant between arms. Females, those with prior HPV vaccinations, and those seen at urban clinics had significantly higher odds of HPV vaccination in adjusted models. DISCUSSION: CDS may require optimization for young adults to significantly impact HPV vaccination. TRIAL REGISTRATION: clinicaltrials.gov NCT02986230, 12/6/2016.