Background: One barrier to the efficacy of vaccines in advanced PCa may be the presence of cancer-associated IS. Poly-IC:LC (PICLC), a potent immune adjuvant, can reverse IS in other malignancies; we studied its effects in boosting the immunologic response to a MUC-1 peptide vaccine. Methods: A single arm study was conducted to determine the efficacy of PICLC. Eligible pts had advanced PCa with evidence of systemic IS, defined as low levels of IFN-γ and TNF-α production by peripheral blood mononuclear cells. On weeks 1 and 2, pts were treated with PICLC 25μg/kg, 3 days per week. On weeks 3, 5, and 7, pts were treated with injections of MUC-1 vaccine. They continued to receive PICLC twice weekly till progression. Cytokine levels were measured prior to treatment and at week 3. The primary endpoint was an increase in levels of IFN-γ and TNF-α in > 40% of pts. Cytokine levels in CD4/CD8 T-cell subsets, anti-MUC-1 IgM and IgG levels, and serial PSAs were secondary endpoints. Results: Fourteen pts with advanced PCa were enrolled, with 13 being castrate-resistant. Their ages ranged from 51 to 80 years (median 72). 12 of 14 pts (86%) had increased TNF-α production; 9 of 14 (64%) had an increase in IFN-γ; and 9 pts (64%) upregulated both cytokines. 2 of these 9 (22%) pts maintained stable PSA levels for at least 6 months following therapy. The level of response ranged from 15% to 76% for IFN-γ and 9% to 137% for TNF-α. Of the 14 pts, 2 (14%) upregulated IFN-γ in CD4 T-cells and 5 (38%) in CD8 T-cells. TNF-α upregulation was observed equally in CD4/CD8 subsets in 8 (57%) pts. IgM and IgG anti-MUC-1 antibody responses were seen in 3 (21%) pts, with these pts also demonstrating increases in both IFN-γ and TNF-α. PICLC was well tolerated with primary side-effect being mild flu-like symptoms in 10 of 14pts (71%). Conclusions: PICLC (25μg/kg) successfully reversed IS in 9 of 14 (64%) pts with advanced PCa. This, coupled with the encouraging immune and clinical responses observed in some pts, warrants further investigation of PICLC as a vaccine adjuvant in advanced PCa.