Evidence is emerging that interdaily meal pattern variability potentially affects response such as thermic effect of food (TEF), macronutrient metabolism, and appetite. To investigate the effect of irregular meal pattern on TEF, glucose, insulin, lipid profile, and appetite regulation in women who are overweight or with obesity and confirmed insulin resistance. In a randomized crossover trial, 9 women mean ± SD BMI (in kg/m2): 33.3 ± 3.1 with confirmed insulin resistance consumed a regular (14 d; 6 meals/d) and an irregular (14 d; 3–9 meals/d) meal pattern separated by a 14-d washout interval. Identical foods were provided during the interventions, and at the start and end of each meal pattern, participants attended the laboratory after an overnight fast. Energy expenditure, glucose, insulin, lipids, adiponectin, leptin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin were measured at baseline and for 3 h after consumption of a test drink, after which an ad libitum test meal was offered. Subjective appetite ratings were recorded before and after the test drink, after the ad libitum meal, and during the intervention. Continuous interstitial glucose monitoring was undertaken for 7 consecutive days during each intervention. TEF (over 3 h) was significantly lower postirregular intervention compared with postregular (97.7 ± 19.2 kJ*3 h in postregular visit and 76.7 ± 35.2 kJ*3 h in postirregular visit, paired t test, P = 0.048). Differences in HOMA-IR between the 2 interventions (3.3 ± 1.7 and 3.6 ± 1.6 in postregular and postirregular meal pattern, respectively) were not significant. Net incremental AUC for GLP-1 concentrations (over 3 h) for the postregular meal pattern were higher (864.9 ± 456.1 pmol/L*3 h) than the postirregular meal pattern (487.6 ± 271.7 pmol/L*3 h, paired t test, P = 0.005). Following a 14-d period of an irregular meal pattern, TEF was significantly less than following a regular meal pattern, potentially compromising weight management if sustained long term. This study was registered at www.clinicaltrials.gov as NCT02582606. ▪