Purpose: To determine the biologic effect of granulocyte-macrophage colony-stimulating factor (sangramostim, GM-CSF; Immunex Corporation, Seattle, WA) as measured by prostate-specific antigen (PSA) kinetics in patients with serologic progression of prostate cancer after definitive local therapy. Patients and Methods: Patients with prostate cancer who had undergone previous definitive surgical or radiation therapy with nonmetastatic, recurrent disease as manifested by a rising PSA between 0.4 ng/mL and 6.0 ng/mL were enrolled on this phase II trial. Patients received 250 μg/m2/day of subcutaneous GM-CSF on days 1 through 14 of a 28-day cycle. PSA was measured at day 1 of each cycle. Results: Thirty patients with serologic progression of prostate cancer were treated. The median pretreatment PSA was 2.9 ng/mL. Of the 29 evaluable patients, three patients (10%; 95% confidence interval, 2% to 27%) achieved a 50% reduction in PSA. For the patients (n = 26) in whom the on-treatment PSA doubling time could be calculated, the median PSA doubling time increased from 8.4 months to 15 months (P = .001), and the median slope of the PSA versus time curve decreased with treatment (P = .004). Therapy was well tolerated by all patients, with an average treatment duration of 16.5 cycles (range, 5 to 33). Conclusion: GM-CSF has a biologic effect in patients with serologic progression of prostate cancer after definitive local therapy, as measured by PSA declines and modulation of PSA kinetics.