OBJECTIVE To investigate the augmentation effect and mechanism of all-trans retinoic acid (ATRA) on the bystander effect of herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) system in the treatment of tongue carcinoma cell line. METHODS Immunocytochemistry and flow cytometry (FCM) were used to analyze the expression of Cx43 protein in Tca8113 cells after treated with ATRA; The bystander effect of HSV-TK/GCV system on tongue carcinoma cells before and after treatment with ATRA was detected by MTT assays. The interaction of ATRA and bystander effect was analyzed by factorial experiment. RESULTS After treated by ATRA (10(-7) mol/L - 10(-5) mol/L), the expression of Cx43 protein was up-regulated in Tca8113 cells and the positive rate of Cx43 protein increased from 5.17% (before treatment) to 30.53% (10(-5) mol/L ATRA). There was significant difference between ATRA treated cells and untreated cells (P < 0.01). The bystander effect of HSV-TK/GCV system on Tca8113 cells was poor, but improved after combined with ATRA. There was cooperation effect between ATRA and bystander effect of HSV-TK/GCV (P < 0.05). CONCLUSIONS ATRA can augment the bystander effect of HSV-TK/GCV system in the treatment of tongue carcinoma cell line. The mechanism might be due to up-regulation of Cx43 gene and restore gap junction intercellular communication.