Background: High stress levels in the parents of infants with colic have negative impacts on their quality of life. Maternal concerns with infants' needs can be reduced through social support. Objectives: The aim of this study was to assess the relationship between social support and perceived stress in the mothers of infants with colic. Methods: This cross-sectional study was carried out on 200 mothers of infants with colic referred to 14 healthcare centers affiliated to Iran University of Medical Sciences in year 2017. A convenience sampling method was used. Demographic data form, Cohen perceived stress and Vaux's perceived social support questionnaires were used for data collection. Descriptive and inferential statistics were used for data analysis. P < 0.05 was considered statistically significant. Results: There was a statistically significant positive correlation between social support and perceived stress (r = 0.31, P = 0.001). In other words, with increase in social support, perceived stress would be increased. However, the support of the spouse in the form of childcare could reduce perceived stress in the mother (P = 0.001). Conclusions: The results of this study showed that with increase in social support, perceived stress in the mothers of infants with colic also would be increased. However, spousal assistant in childcare is accompanied by a reduction in perceived stress in mothers.