Background: Haploidentical hematopoietic cell transplantations (haplo-HCTs) with post-transplant cyclophosphamide (PT-Cy) are standard practice, but complications causing morbidity and mortality are not well described. Methods: The aim of this prospective non-interventional multicenter study was to document frequency of potential non-infectious and infection-related complications and main transplant outcomes after the first unmanipulated haplo-HCT with PT-Cy between 2017 and 2019 in 129 adult patients with hematological malignancies. The median follow-up was 37.3 months [95% CI: 34.3–39.7]. Results: The cumulative incidence (CI) of acute graft versus host disease (aGvHD) at day +100 was 22.4% grade II-IV [95% CI: 15.5–30.1] and 8.8% grade III-IV [95% CI: 4.6–14.6], respectively. The cumulative incidence of chronic GvHD (cGvHD) at 24 months was 25.8% [95% CI: 18.5–33.6]; extensive cGvHD was 10.9% [95% CI: 6.3–17.1], respectively. The most frequent non-infectious complications for the whole study population were mucositis—37.5% (n = 48); renal insufficiency—18% (n = 23); and cardiovascular complications—10.9% (n = 14). The following infection-related complications were diagnosed: bacterial in 84 (65.1%), viral in 66 (51.6%), and fungal in 24 (18.6%) recipients. Two-year OS was 58.1% [95% CI: 50.2–67.3]; NRM—27.1% [95% CI: 19.7–35]; PFS—50.4% [95% CI: 42.5–59.8]; and GRFS—38.8% [95% CI: 31.2–48.1]. About 50% of all deaths were directly caused by infection or infection-related conditions. Conclusions: Disease remission status at transplant significantly affected PFS, chronic GvHD, and GRFS. Although clinical applications of haplo-HCT with PTCy are widespread, the study confirms the need to reduce infection-related mortality after this type of GvHD prophylaxis.