The aim of this retrospective study was to investigate the influence of oxcarbazepine (OCBZ) and methsuximide (MSM) on lamotrigine (LTG) serum concentrations. The effect of OCBZ compared to carbamazepine (CBZ) and the effect of MSM on LTG serum concentrations were examined in patients with and without valproic acid (VPA) comedication. Altogether, 376 samples from 222 patients were analyzed in routine drug monitoring. Two or more serum samples from the same patient were considered only if the comedication had been changed. For statistical evaluation, regression analytical methods and an analysis of variance were performed. For the analysis of variance, the LTG serum concentration in relation to LTG dose/body weight-level-to-dose ratio (LDR), in (µg/mL)(mg/kg)-was calculated and compared for different drug combinations. The nonlinear regression analysis including the LTG dose per body weight, age, gender, and the different kinds of comedication revealed that these variables have a significant influence on LTG serum concentration (r2 = 0.724). The relationship between LTG dose/body weight and serum concentration deviates only slightly from linearity, the LTG concentration was about 18% lower in women than in men, and age had a significant influence. The data indicate that children have significantly lower LTG concentrations than adults on a comparable LTG dose per body weight and that children may be more prone to enzyme induction by comedicated drugs. Methsuximide has a strong inducing effect on the LTG metabolism and decreases the LTG concentrations markedly (about 70% compared to LTG monotherapy). Carbamazepine also reduces the LTG concentrations considerably (by 54%). The inducing effect of OCBZ (29%) was less pronounced but also significant. The inducing effect of MSM, CBZ, and OCBZ was also seen in combination with VPA: VPA alone increases the LTG concentration approximately 211%, whereas in addition to MSM (8%), CBZ (21%), or OCBZ (111%), the increase of LTG was significantly smaller. The analysis of variance confirmed the results of the regression analysis. The effect of MSM on the LTG concentration should be considered if MSM is added or withdrawn in patients treated with LTG. Oxcarbazepine had a less pronounced inducing effect on LTG metabolism compared to CBZ. If CBZ is replaced by OCBZ as comedication, an increase in LTG serum concentrations should be expected.