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Caring for an infant with unexplained, persistent crying is one of the most stressful events for new parents. Infant irritability, also referred to as infantile colic, occurs in 10-25% of all infants and is the most common parental concern reported in the first year of life.The aim of this study was to evaluate the effectiveness of a home-based nursing intervention in reducing parenting stress in three groups of families with irritable infants, using data from a larger evaluation study.A two-site, randomized clinical trial was conducted with 121 infants and their parents. Infants were randomized to a treatment or a control group. A third group of infants (n = 43) was added as a posttest-only comparison. The level of parenting stress was measured by the Parenting Stress Index (PSI) at baseline, after the 4-week intervention, and at the 8-week follow-up visit.A repeated measures analysis of variance (ANOVA) was used to compare the two groups across the three time points (baseline, immediately after the 4-week intervention, and at the 8-week follow-up visit). The results revealed a reduction in total parenting stress over time for both the treatment and control groups. Mothers in the treatment group reported reduced parenting stress on the parent-child dysfunctional interaction subscale (p = .04). Total parenting stress scores were found to be significantly higher for mothers in the posttest-only group (p = .009).Initial parenting stress levels were high in all participants. Parent feedback at the exit interview indicated that the nurse visits for data collection were also viewed as helpful in reducing the stress level associated with parenting these irritable infants. This home-based program was perceived as helpful in improving the interactions between parents and their irritable infants.