BACKGROUND: There is a felt need for trying newer therapeutic modalities in patients with chronic spontaneous urticaria, especially in the subset of patients classified as non-responders to antihistamines. Autologous serum therapy is an upcoming modality of treatment, and we decided to study its efficacy by subcutaneous route. AIMS: To evaluate the effectiveness of subcutaneous autologous serum therapy (AST) in CSU. METHODS: This was a single blind, placebo-controlled parallel group, randomized, controlled study. Twenty-four patients with CSU (11M: 13 F) were given subcutaneous AST and seventeen patients (7 M: 10F) patients were given subcutaneous injection normal saline (placebo), along with levocetirizine in an on-demand basis in both groups. RESULTS: Urticaria activity score (UAS) came down from 35.74 to 7 at the end of 9 weeks and the patients' requirement of antihistamines also reduced remarkably from 5.8 to 1.7 per week in the serum group. Sub-cutaneous saline group did not show statistically significant fall in UAS. Saline group showed UAS 32.8 at zero week to 22.1 at the end of 9 weeks. DLQI showed significant fall in serum group, from 14.26 to 4 at the end of 9 weeks. CONCLUSION: Subcutaneous autoserum therapy is effective in treatment of CSU.