Background: There are some evidences that indicate there are sexual differences in drug abuse and response to synthetic and herbal drugs. It has been shown that the expression of C-FOS increases in many areas of brain during morphine withdrawal. Concerning the sedative effect of Matricaria recutita extract, the aim of this study was to compare expression of C-FOS transcription factor during morphine withdrawal with and without acute administration of Matricaria recutita on male and female adult mice.Materials and Methods: This study was done at Shahid Chamran University of Ahvaz in 2007 on NMRI mice. Male and female mice were assigned into 8 groups (morphine + saline; morphine + naloxone; morphine + Matricaria recutita + naloxone; and morphine + saline + naloxone). To develop morphine dependency, increasing doses of morphine (20, 40, 80 mg/kg injected subcutaneously) for 4 days. Mice received a final morphine injection (40 mg/kg) 3hours prior to naloxone (5 mg/kg) on the day of testing (day 4). Matricaria recutita extract whit a dose of 30 mg/kg was administered intraperitoneally 5 minutes before naloxone injection. In cellular study, 90minute after naloxone injection, mice were decapitated and their brains were separated, then mRNA was extracted from brain tissue. Using DIG-labeled DNA probe of C-FOS, beta-actin and dot blot technique, expression of C-FOS was analyzed by Zero Dscan software. Statistical evaluation of data was performed using student t-test and ANOVA with one factor followed by Duncan test in SPSS software. P values less than 0.05 were considered significant. Results: The rate of expression of C-FOS increased in male mice but decreased significantly in female mice after naloxone-precipitated abstinence) P<0.01). Matricaria recutita attenuated the rate of expression of C-FOS in male mice but it showed synergistic effect on it in female mice (P<0.05).Conclusion: It seems that the cellular processes involving morphine dependenc and response to treatment with Matricaria recutita are sex dependent and are affected by sexual hormones.