Signal transduction has been reported to be involved in antidepressant treatment outcomes; however, its mechanisms remain unclear. The aims of this study were to explore the associations between antidepressant remission and single nucleotide polymorphisms (SNPs), haplotypes, and gene–gene interactions in the Ras–Raf–MAPK intracellular signaling pathway. A total of 302 inpatients with major depressive disorder (DSM-IV Axis I) were assessed using the 17-item Hamilton Depression Rating Scale before and after 8 weeks of antidepressant treatment to determine the remission rate in the samples. Twenty-four SNPs at five kinase genes (Ras–Raf–MEK–ERK–RSK), which are a part of the Ras–Raf–MAPK signaling pathway, were identified to investigate a genetic association with antidepressant drug outcome. Correlations between 24 SNPs at the five kinase genes in the Ras–Raf–MAPK signaling pathway and antidepressant drug outcome were not found. The percentage of the CCAGA haplotype that RSK(2/3/4)–RSKL(1/2) gene loci SNPs constructed was markedly lower in the remitter group when compared with the nonremitter group in female depressed patients (P=0.04), whereas the proportion of AAAGGG haplotype that RSK(2/3/4)–RSKL(1/2) gene loci SNPs constructed in the remitter group was significantly greater than that in the nonremitter group in male patients (P=0.02). In addition, MEK1 (rs28730804) and RSK3 (rs2229712) in the Ras–Raf–MAPK signaling pathway showed a gene–gene interaction that affected antidepressant drug outcome in female depressed patients (P=0.041). Although this study did not find that SNPs at the five kinase genes in the Ras–Raf–MAPK signaling pathway are important markers for antidepressant outcome, certain haplotypes that SNPs at the RSK(2/3/4)–RSKL(1/2) gene constructed may be important markers for antidepressant drug efficacy. We observed a gene–gene interaction in this signaling pathway that influenced antidepressant efficacy in female depressed patients. Therefore, it is likely that in female depressed patients, different haplotypes and gene–gene interaction in the Ras–Raf–MAPK signaling pathway are involved in mediating the pharmacological action of an antidepressant, and eventually influence antidepressant efficacy.