Recent research has shown more favorable training adaptations for inactive adults when cardiorespiratory fitness (CRF) exercise is prescribed with the use of ventilatory thresholds compared to percentages of heart rate reserve (HRR). However, there is limited research on changes in health-related outcomes with the use of these CRF methods in combination with muscular fitness exercises. The objective of this study was to compare the effectiveness of two training programs for improving CRF, muscular fitness, and cardiometabolic risk factors. Inactive men and women (n=109, aged 49.3±15.5 years) were randomized to a non-exercise control group or one of two exercise training groups. The exercise training groups consisted of 13 weeks of structured exercise with progression using either CRF exercise prescribed with the use of ventilatory thresholds and functional training for muscular fitness (THRESH group) or HRR and traditional muscular fitness training (STND group). After the 13-week protocol, there were significant differences in body weight, body composition, systolic blood pressure, high-density lipoprotein cholesterol (HDL-c), VO2max, 5-repetition maximum (RM) bench press, and 5-RM leg press for both treatment groups compared to the control group after controlling for baseline values. However, the THRESH group had significantly more desirable outcomes for VO2max, 5-RM bench press, 5-RM leg press, body composition, and HDL-c when compared to both the STND and control group. Additionally, the proportion of individuals estimated as likely to respond above 3.5 mL·kg-1·min-1 in VO2max (i.e., the minimal clinically important difference) was 76.4%, 20.8%, and 0.13% for the THRESH, STND, and control groups, respectively. While both exercise programs elicited favorable health-related adaptations after 13 weeks, these results suggest that a personalized program with exercise prescribed based on ventilatory threshold and with the use of functional muscular fitness training may yield greater training adaptations.