This retrospective study was launched to evaluate the efficacy of doxycycline and to find independent predictors of a clinical response in patients with ocular adnexal lymphoma of mucosa-associated lymphoid tissue (OAML). Thirty-eight patients with newly diagnosed, localized OAML received doxycycline for 3 weeks (12 patients) or 6 weeks (26 patients). Clinical factors including absolute lymphocyte count (ALC) and neutrophil count (ANC) were compared between responders and non-responders. After a median follow-up of 26.4 months, doxycycline resulted in an overall response rate of 47% and a 3-year time-to-treatment failure (TTF) rate of 84%. Patients treated with doxycycline for 6 weeks versus 3 weeks tended to have a higher response rate (54%vs 33%). Absolute lymphocytosis (ALC > 3.01 x 10(9)/L) and absolute neutrophilia (ANC > 1.92 x 10(9)/L) were defined based on the median value of each count. Patients with (19 patients) versus without absolute lymphocytosis had significantly shorter 2-year TTF (70%vs 100%, P = 0.021) and a lower response rate (32%vs 63%, P = 0.051). Absolute lymphocytosis (odds ratio [OR] = 4.7; 95% confidence interval [CI], 1.1-20.8; P = 0.043) and non-conjunctival tumor (OR = 11.8; 95% CI, 1.1-122.5; P = 0.038) were negative predictors for response by multivariate analysis. Front-line doxycycline is effective particularly in localized OAML patients without absolute lymphocytosis but with conjunctival involvement.