No approved medical therapies prevent progression of low-grade prostate cancer (PCa). Rapamycin inhibits cell proliferation and augments immune responses, producing an antitumor effect. Encapsulated rapamycin (eRapa) incorporates rapamycin into a pH-sensitive polymer, ensuring consistent dosing. Here, we present results from a phase I trial evaluating the safety and tolerability of eRapa in patients with PCa. Patients with Gleason <=7 (3+4) disease (low- and intermediate-risk) under active surveillance were enrolled in a 3+3 study with three eRapa dosing cohorts (cohort 1: 0.5mg/week; cohort 2: 1.0 mg/week; and cohort 3: 0.5mg/day). Patients were treated for three months and followed for an additional three months to assess safety, pharmacokinetics, quality of life (QoL), immune response, and disease progression. Fourteen patients (cohort 1: n=3; cohort 2: n=3; cohort 3: n=8) were enrolled. In cohort 3, one dose-limiting toxicity (DLT; neutropenia) and two non-DLT grade 1-2 adverse events (AEs) occurred that resulted in patient withdrawal. All AEs in cohorts 1-2 were grade 1. Peak serum rapamycin concentration was 7.1ng/mL after a 1mg dose. Stable trough levels (~2.0ng/mL) developed after 48-72 hours. Daily dosing mildly worsened QoL, though QoL recovered after treatment cessation in all categories except fatigue. Weekly dosing increased naïve T-cell populations. Daily dosing increased central memory cell populations and exhaustion markers. No disease progression was observed. In conclusion, treatment with eRapa was safe and well-tolerated. Daily dosing produced higher frequencies of lower-grade toxicities and transient worsening of QoL, while weekly dosing impacted immune response. Future studies will verify clinical benefit and long-term tolerability.