Background/Objective <p>Obesity imposes dysfunction of the endogenous cellular reparative system, which may manifest as impaired adipose tissue-derived mesenchymal stem/stromal cells (AT-MSCs) function or altered characteristics of circulating endothelial progenitor cells (EPCs). However, whether both systems are abnormal in patients with obesity remains unclear. We hypothesized that human obesity induces impairment of MSCs and EPCs that would be reversed after weight-loss surgery (WLS).</p> Methods <p>Abdominal adipose tissue and peripheral blood mononuclear cells were collected to harvest MSCs and EPCs, respectively, from patients with obesity (<i>n</i> = 8) before and 9–12 months after WLS. MSCs mitochondrial function and EPCs number and surface markers were compared to those collected from healthy controls (HC).</p> Results <p>Patients with obesity had a higher basal body mass index compared to both HC (<i>P</i> &lt; 0.0001) and post-WLS (<i>P</i> &lt; 0.001). Compared to HC, MSC proliferative and differentiation capacity was preserved (<i>P</i> &gt; 0.05), but they showed at baseline increased mitochondrial oxidative stress, and cytochrome-c release (<i>P</i> &lt; 0.05), with reduced membrane potential and matrix density, which mostly improved after WLS. The percent of circulating CD34⁺KDR⁺CD133⁺ and CD34⁺KDR⁺ EPCs was elevated in patients with obesity (<i>P</i> &lt; 0.05), as were EPC fractions expressing the inflammatory marker VAP-1 or pro-calcinogenic marker OCN-1, yet neither fell after WLS (<i>P</i> &gt; 0.05).</p> Conclusion <p>Obesity impairs MSC mitochondrial function and increases the percent of circulating, but also potentially injurious EPCs. WLS largely reverses MSC mitochondrial injury and but not circulating EPC characteristics. Therefore, restoration of the endogenous tissue-resident and circulating cellular regenerative systems in the same patients with obesity may require different strategies or timeframes.</p>