The purpose of the present study was to describe associations between the use of common over-the-counter (OTC) and prescription medications with individual differences in salivary cortisol in infants and their mothers. Participants were 1020 mothers and 852 infants (52.5% boys; ages 5.03–13.44 months) from economically disadvantaged and ethnically diverse families (38.4% African American) who donated saliva samples before, 20 and 40 min after infants participated in a series of challenging tasks. Samples (N = 5616) were later assayed for cortisol. Medication information was content analyzed separately for infants (e.g., teething gels, nonsteroidal anti-inflammatory drugs, acetaminophen, decongestants) and mothers (e.g., narcotics, antidepressants, antipsychotics, contraceptives, glucocorticoids). A large percentage of infants (44%) and the majority of mothers (57.5%) had used at least one medication (range 0–4) in the previous 48 h. Most frequent were acetaminophen (e.g., Tylenol®) and cold medications (e.g., decongestants) for infants and contraceptives and acetaminophen for mothers. Compared to infants not taking any medications, cortisol reactivity to the challenge tasks was less pronounced for infants taking acetaminophen. Cortisol levels were higher for mothers taking oral or transdermal contraceptives and acetylsalicylic acid (e.g., Aspirin®) but lower for mothers taking pure agonist opioids (e.g., Oxycontin®) compared to mothers not taking any medications. These medication-related differences remained significant after controlling for sampling time, fever, maternal anxiety and depression, infant temperament, ethnicity, SES, and health status. Recommendations are provided to steer investigators clear of these potential sources of unsystematic error variance in salivary cortisol.