Importance: Adolescent well care visits provide opportunities for clinicians to facilitate parent-adolescent communication (PAC) to reduce pregnancy, sexually transmitted infections, and alcohol-related harm among adolescents. Objective: To test the effect of brief parent-targeted interventions delivered in primary care settings on PAC about sexual and alcohol use behaviors. Design, Setting, and Participants: Randomized clinical trial conducted at a primary care pediatric practice from January 4, 2016, to April 10, 2017. Adolescents who were scheduled for a well care visit were recruited, along with their parent or guardian. Data analyses continued through April 30, 2018. Interventions: During well care visits, parents in sexual health intervention and alcohol prevention intervention groups received coaching to discuss written intervention materials encouraging PAC about sex or alcohol, respectively, with their adolescent within 2 weeks, followed by a brief clinician endorsement. After 2 weeks, parents received a follow-up telephone call. Control group parents received usual care. Main Outcomes and Measures: Participants were surveyed 4 months after the well care visit. Parent-reported and adolescent-reported quality of PAC was measured using the 20-item Parent-Adolescent Communication Scale, in which a higher score indicates better PAC; and frequency of PAC about sex or alcohol was measured using a 4-point Likert-type scale with 1 indicating not at all or never, and 4 indicating a lot or often. Results: Of 196 parent-adolescent dyads assessed for eligibility, 118 (60.2%) were eligible to participate. These 118 dyads were randomized to 1 of 3 groups: (1) sexual health intervention (n = 38 [32.2%]); (2) alcohol prevention intervention (n = 40 [33.9%]); and control (n = 40 [33.9%]); 104 parents (88.1%) and 99 adolescents (83.9%) completed the study. Parents included 112 women (94.9%) and had a mean (SD) age of 45.8 (6.9) years. Adolescents included 60 girls (50.9%); 67 adolescents (56.8%) were aged 14 years, and 51 adolescents (43.2%) were aged 15 years. Participant race/ethnicity reflected that of the practice (63 black adolescents [53.4%]; 46 white adolescents [38.9%]; 111 non-Hispanic adolescents [94.1%]). At baseline, 15 adolescents (12.7%) reported a history of sexual behavior and 16 adolescents (13.6%) reported a history of alcohol use. Intention-to-treat analyses found that 4 months after the intervention, adolescents in the sexual health intervention group reported a higher mean frequency score for PAC about sex compared with those in the control group (2.32 [95% CI, 1.97-2.66] vs 1.79 [95% CI, 1.50-2.08]; P = .02); adolescents in the alcohol prevention intervention group reported a higher mean frequency score for PAC about alcohol compared with those in the control group (2.93 [95% CI, 2.60-3.25] vs 2.40 [95% CI, 2.08-2.72]; P = .03). Parent-reported frequency scores for PAC about sex or alcohol did not differ by group. Conclusions and Relevance: Brief parent-targeted interventions in primary care settings increased adolescent-reported frequency of PAC about sexual health and alcohol use and may be an important strategy for parents to influence adolescent behaviors and health outcomes. Trial Registration: ClinicalTrials.gov identifier: NCT02554682.