We retrospectively evaluated the outcome of oral low-dose dexamethasone (DXM) therapy for androgen-independent prostate cancer (AIPC). Between January 1999 and April 2006, 99 consecutive patients with AIPC were enrolled in this study. The median patient age was 70 years (range 46-86), and the median pretreatment prostate-specific antigen (PSA) level was 243 ng/ml (range 8.2-29600). Median follow-up was 41.9 months (range 11.4-170.4). Upon biochemical failure, patients were treated with oral low-dose DXM. A total of 40 of the 99 cases (40.4%) showed a ≥50% decrease in serum PSA levels (PSA responders). Twenty-five cases (25.2%) showed a <50% decrease in PSA, and the remaining 34 cases (34.3%) had increased PSA levels (PSA non-responders). The median PSA progression-free survival was 3.0 (range 0-27) and 8.0 months (range 2-27) for the entire cohort and PSA responders, respectively. The PSA responders had a significantly increased survival (median 30.1 months) compared to the non-responders (median 8.8 months, P<0.001). Of the 34 patients who were under pain control for bone metastases before the administration of DXM, 23 (67.6%) were able to discontinue the regular use of analgesics. The PSA responders also showed an increase in hemoglobin levels. The change in serum interleukin-6 levels was significantly associated with a response to DXM (P=0.0065). Severe adverse events of DXM were rare. Clinicopathological factors predicting the PSA response to DXM were age, time from initial androgen deprivation therapy to DXM and PSA velocity prior to DXM. In conclusion, oral low-dose DXM led to an acceptable PSA response in patients with AIPC. Thus, this therapy may be an effective and safe alternative for the treatment of AIPC, particularly for patients who are not favourable candidates for chemotherapy.