Objective To evaluate the sensitivity to change of daily ratings of the comfort (COMF) and behavioral/emotional health (BEH) domains of the Infants with Clefts Observation Outcomes Instrument (iCOO) at 3 time points, and to assess the association of post-surgical interventions on iCOO ratings. Design The COMF and BEH domains were completed by caregivers before (T0), immediately after (T1), and 2-months after (T2) cleft lip (CL) surgery. Analyses included descriptive statistics, correlations, t-tests, and generalized estimating equations. Participants Caregivers ( N = 140) of infants with CL with/without cleft palate. Main Outcome Measures The COMF and BEH domain scores of the iCOO: Scale (SCALE), a summary of observable signs; and Global Impression (IMPR), a single item measuring caregivers’ overall impression. Results Daily COMF and BEH SCALE and IMPR scores changed significantly during T1 ( P's 0.05). After CL surgery, the combined use of immobilizers and nasal stents and the use of multiple feeding methods with treatment for gastroesophageal reflux were associated with lower daily scores in COMF and BEH SCALE and IMPR ( P's: 0.040 to Conclusions COMF and BEH iCOO scores were sensitive to daily changes in infant well-being following CL surgery. Future studies should further investigate impact of post-surgical treatments on infant well-being.