Background <p>Multimodal treatment has been suggested to improve outcomes in retroperitoneal soft tissue sarcoma (RPS). This study assessed the impact of neoadjuvant radiotherapy, chemotherapy, and the combination with regional hyperthermia (RHT) on postoperative morbidity using the Comprehensive Complication Index (CCI).</p> Patients and Methods <p>This single-center retrospective cohort study analyzed 335 surgeries for primary and recurrent RPS (2009–2022). The primary outcome was CCI, which was modeled using zero-one inflated beta regression. Predictors included age, sex, recurrence, transfusion needs, and the number of resected organs.</p> Results <p>Patients with neoadjuvant radiotherapy (CCI, 32.79 ± 25.24 vs 22.76 ± 26.75), neoadjuvant chemotherapy (28.06 ± 24.35 vs 23.55 ± 27.75), and the combination of neoadjuvant chemotherapy + RHT (31.52 ± 25.78 vs 22.54 ± 26.42) had higher CCI scores compared with patients without these treatments. In multivariable models of the probability of a complication (CCI &gt; 0) or of the severity (0 &lt; CCI &lt; 100) these neoadjuvant treatments did not significantly influence CCI. The resection of &gt; 3 organs was associated with more frequent (<i>p</i> = 0.004) and more severe (<i>p</i> = 0.002) complications, as were blood transfusions (CCI &gt; 0, <i>p</i> = 0.030; 0 &lt; CCI &lt; 100, <i>p</i> = 0.034). When the interaction between therapy and recurrence was added to these models, the combination of radiotherapy and chemotherapy (without RHT, <i>n</i> = 7) was associated with higher morbidity, whereas all other protocols appeared to be equally safe in primary and recurrent cases.</p> Conclusions <p>Postoperative morbidity is driven by surgical factors, particularly transfusions and multivisceral resections, rather than multimodal neoadjuvant therapies. Intensive protocols, including RHT, are safe for patients with RPS from a surgical perspective.</p>