Background and Objectives: The parents in families with a mentally retarded child tolerate psychological consequences in addition to financial and social issues. The mothers of these children are usually exposed to various harms and severe environmental stresses that can be exacerbated or facilitated by different factors. Therefore, this study aimed to predict the perceived stress of mothers with mentally retarded children based on spirituality and five personality traits. Methods: This correlational study included all mothers with mentally retarded children in Qom, Iran, in the academic year 2018-19. The study participants (n=150) were selected using the random sampling method, and the data collection was conducted using Cohen’ s Perceived Stress Scale, Parsian and Dunning Spirituality Questionnaire, and NEO Personality Inventory. The obtained data were then analyzed in SPSS software (version 23) through Pearson correlation coefficient and Multivariate Linear Regression. Results: The results of the c test revealed a significant positive correlation between perceived stress and the self-awareness component of spirituality (P=0. 03; R=0. 18). Moreover, there was a significant positive correlation between the perceived stress and five factors of personality, including neuroticism (P=0. 001; R=0. 29), extraversion (P=0. 03; R=0. 18; ), openness to experience (P=0. 02; R=0. 19), agreeableness (P=0. 03; R=0. 17), and conscientiousness (P=0. 02; R=0. 19). The results of regression test indicated that self-awareness (R 2 =0. 058) as a component of spirituality and neuroticism (R 2 =0. 097), as a personality trait, were two predictors of perceived stress of mothers with mentally retarded children. Conclusion: Based on the results, spiritualism, especially the self-awareness factor, and five personality traits, especially neuroticism, were the good predictors of the perceived stress of mothers with mentally retarded children. Therefore, identification of personality traits that cause stress in mothers with mentally retarded children, and provision of socio-psychological supports to them, especially in form of spiritual programs, can improve the mental health of these mothers.