This study investigated psychosocial factors thought to be associated with perceived stress over the course of infertility treatment. The research was based on secondary analysis of data from the Study of Marriage, Family, and Life Quality with a sample of 128 people who completed an infertility-related stress instrument at all three measurement intervals (1988, 1999, and 1990). Self-esteem and perceived health were associated with stress at the study baseline, importance of a biological family and extent of spousal support associated with stress at the 12-month follow-up, and factors pertaining to infertility treatment (number of treatments, relationship with physicians) associated with stress at the 24-month follow-up. Self-esteem was the only psychosocial factor associated with change in stress over the course of treatment. Social workers and health care professionals should be sensitive to the emotional experiences of couples during infertility treatment. Identifying factors explaining stress, or that may be targets for intervention, has significance for social workers in health care and other settings.