Objectives. To evaluate Chicas Creando Acceso a la Salud (Girls Creating Access to Health; ChiCAS), a Spanish-language, small-group intervention designed to increase preexposure prophylaxis (PrEP) use, consistent condom use, and medically supervised gender-affirming hormone therapy use among Spanish-speaking transgender Latinas who have sex with men. Methods. Participants were 144 HIV-negative Spanish-speaking transgender Latinas, aged 18 to 59 years, living in North and South Carolina. From July 2019 to July 2021, we screened, recruited, and randomized them to the 2-session ChiCAS intervention or the delayed-intervention waitlist control. Participants completed assessments at baseline and 6-month follow-up. Follow-up retention was 94.4%. Results. At follow-up, relative to control participants, ChiCAS participants reported increased PrEP use (adjusted odds ratio [AOR] = 4.64; 95% confidence interval [CI] = 1.57, 13.7; P < .006). However, ChiCAS participants did not report increased use of condoms or medically supervised gender-affirming hormone therapy. ChiCAS participants reported increases in knowledge of HIV (P < .001), sexually transmitted infections (P < .001), and gender-affirming hormone therapy (P = .01); PrEP awareness (P < .001), knowledge (P < .001), and readiness (P < .001); condom use skills (P < .001); and community attachment (P < .001). Conclusions. The ChiCAS intervention was efficacious in increasing PrEP use among Spanish-speaking, transgender Latinas in this trial. (Am J Public Health. 2024;114(1):68-78. https://doi.org/10.2105/AJPH.2023.307444).