This study examined the effects of high-intensity interval training (HIIT; 30 s sprint, 4–5 min passive recovery) and prolonged intermittent sprint training (PIST; 10 s sprint, 2–3 min moderate exercise) on the systemic inflammatory markers C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α), aerobic capacity, and anthropometry in a middle-aged, sedentary population. Methods: Fifty-five sedentary adults (age 49.2 ± 6.1 years) were randomised into HIIT (n = 20), PIST (n = 21), or a sedentary control group (CTRL n = 14). HIIT and PIST performed three training sessions per week for 9 weeks on a cycle ergometer, matched for total high-intensity time, while CTRL continued normal sedentary behaviours. Pre- and post-intervention testing involved measures of anthropometry, peak oxygen consumption (VO2peak), and venous blood collection for analyses of CRP and TNF-α. Results: HIIT and PIST increased VO2peak compared to CTRL (+3.66 ± 2.23 and 3.74 ± 2.62 mL kg min−1). A group × time interaction (p = 0.042) and main effect of time (p = 0.026) were evident for waist girth, with only HIIT showing a significant reduction compared to CTRL (−2.1 ± 2.8 cm). TNF-α and CRP showed no group × time interaction or time effect (p > 0.05). Conclusions: In sedentary individuals, 9 weeks of HIIT or PIST were effective to improve aerobic capacity; however, only HIIT significantly reduced waist girth and WHR compared to CTRL. Markers of systemic inflammation remained unchanged across all groups. Accordingly, for inflammation and VO2peak, the distribution of sprints and the active or passive recovery periods are inconsequential provided that total duration of high-intensity efforts is similar.