BACKGROUND: Circadian rhythms underlie many immune responses and allergic diseases. Subcutaneous immunotherapy (SCIT) can result in adverse reactions; however, it is unclear whether such reactions have a diurnal pattern. OBJECTIVE: To assess whether the timing of SCIT affects the rate of adverse reactions. METHODS: This study was a retrospective medical record review of adult patients (n = 289) who received SCIT at the Northwestern Medical Faculty Foundation, Chicago, Illinois, during a 10-year period (2004-2014). Injections were given in the outpatient setting. There were a total of 17,457 injections with 574 reactions. Covariates included age, sex, median income, asthma status, vial contents, number of injections, and previous immunotherapy reactions. Logistical regression was used to calculate the odds of having a reaction with time of SCIT administration as the primary determinate. RESULTS: Immunotherapy reactions occurred more frequently after afternoon or evening (pm) injections (328/8721 = 3.8%) vs morning (am) injections (246/8736 = 2.8%), (chi2 = 12.26, P < .01). Systemic reactions, defined as World Allergy Organization grade 1 or higher, did not have diurnal variation (59/8721 = 0.67% for pm vs am 56/8736 = 0.64% for morning; chi2 = 0.08; P = .77). pm injections resulted in higher odds of reaction compared with am injection in a fully adjusted logistic regression model (odds ratio = 1.43; 95% confidence interval, 1.20-1.70; P < .01). When considering time as 4 categories, the highest odds of reaction were noted for the period from 15:01 to 17:30 (odds ratio, 1.55; 95% confidence interval, 1.21-2.00; P < .01). CONCLUSION: pm injections of SCIT are associated with increased cutaneous reaction rates when compared with am injections. In patients experiencing bothersome local reactions, it may be beneficial to administer SCIT in the morning.