Objectives: The purpose of this study was to investigate the effect of 16 weeks of Bikram yoga on perceived stress, self-efficacy and health related quality of life (HRQoL) in sedentary, stressed adults. Design: 16 week, parallel-arm, randomised controlled trial with flexible dosing. Methods: Physically inactive, stressed adults (37.2 ± 10.8 years) were randomised to Bikram yoga (three to five classes per week) or control (no treatment) group for 16 weeks. Outcome measures, collected via self-report, included perceived stress, general self-efficacy, and HRQoL. Outcomes were assessed at baseline, midpoint and completion. Results: Individuals were randomised to the experimental (n = 29) or control group (n = 34). Average attendance in the experimental group was 27 ± 18 classes. Repeated measure analyses of variance (intention-to-treat) demonstrated significantly improved perceived stress (p = 0.003, partial η2 = 0.109), general self-efficacy (p = 0.034, partial η2 = 0.056), and the general health (p = 0.034, partial η2 = 0.058) and energy/fatigue (p = 0.019, partial η2 = 0.066) domains of HRQoL in the experimental group versus the control group. Attendance was significantly associated with reductions in perceived stress, and an increase in several domains of HRQoL. Conclusions: 16 weeks of Bikram yoga significantly improved perceived stress, general self-efficacy and HRQoL in sedentary, stressed adults. Future research should consider ways to optimise adherence, and should investigate effects of Bikram yoga intervention in other populations at risk for stress-related illness. Trial registration: Australia New Zealand Clinical Trials Registry ACTRN12616000867493. Registered 04 July 2016. URL: http://www.anzctr.org.au/ACTRN12616000867493.aspx.