Respiratory depression is a common adverse effect of propofol and remifentanil. We aimed to develop a model for respiratory depressant effects of propofol with remifentanil in patients undergoing endoscopy with sedation. Data were available for 136 patients undergoing endoscopy with sedation. Participants randomly received infusions of propofol and remifentanil. Predicted plasma concentrations, outputted by infusion pumps, were available. Transcutaneous arterial pressure of carbon dioxide (pCO₂) was measured. Data were analyzed using nonlinear mixed-effects modeling methods. Covariate relationships were investigated for age, noxious stimuli (endoscopy tube insertion), and A118G genotype for the <i>µ</i>-opioid receptor (OPRM1). Participants had a median (range) age of 64.0 (25.0–88.0) years, weight of 70.0 (35.0–98.0) kg, and height of 164.0 (147.0–190.0) cm. Seven percent were recessive homozygous for OPRM1 polymorphism. An indirect-effect model with a "modulator" compartment best described pCO₂ data (<i>P</i> &lt; 0.001) over a direct-effect model. Remifentanil inhibited pCO₂ removal with an IC₅₀ of 1.13 ng/ml and first-order rate constant (<i>k_e</i>₀) of 0.28 minute⁻¹. Propofol affected the modulator compartment with an IC₅₀ of 4.97 <i>µ</i>g/ml (no effect-site compartment). Propofol IC₅₀ and remifentanil <i>k_e</i>₀ were reduced with increasing age. Noxious stimuli and genotype were not significant covariates. An indirect-effect model with a rebound mechanism can describe remifentanil- and propofol-induced changes in pCO₂ in patients undergoing noxious procedures. The model may be useful for identifying optimal dosing schedules for these drugs in a combination that provides adequate sedation but avoids respiratory depression.