Although autodialer centralized reminder and recall (C-R/R) from state immunization information systems (IISs) has been shown to raise childhood vaccination rates, its impact on human papillomavirus (HPV) vaccination rates is unclear. In a 4-arm pragmatic randomized controlled trial across 2 states, we randomly selected practices representative of the specialty (pediatrics, family medicine, and health center) where children received care. Within each practice, patients 11 to 17.9 years old who had not completed their HPV vaccine series (NY: N = 30 616 in 123 practices; CO: N = 31 502 in 80 practices) were randomly assigned to receive 0, 1, 2, or 3 IIS C-R/R autodialer messages per vaccine dose. We assessed HPV vaccine receipt via the IIS, calculated intervention costs, and compared HPV vaccine series initiation and completion rates across study arms. In New York, HPV vaccine initiation rates ranged from 37.0% to 37.4%, and completion rates were between 29.1% and 30.1%, with no significant differences across study arms. In Colorado, HPV vaccine initiation rates ranged from 31.2% to 33.5% and were slightly higher for 1 reminder compared with none, but vaccine completion rates, ranging from 27.0% to 27.8%, were similar. On adjusted analyses in Colorado, vaccine initiation rates were slightly higher for 1 and 3 C-R/R messages (adjusted risk ratios 1.07 and 1.04, respectively); completion rates were slightly higher for 1 and 3 C-R/R messages (adjusted risk ratios 1.02 and 1.03, respectively). IIS-based C-R/R for HPV vaccination did not improve HPV vaccination rates in New York and increased vaccination rates slightly in Colorado.