First-derivative spectrophotometry, applying the peak-zero method, was developed for the determination of rosiglitazone (RSG) in coated tablets. The solutions of standard and sample were prepared in ethanol. Quantitative determination of the drug was performed at 331.4 nm (N = 4; delta lambda = 3.2 nm) and was evaluated for the parameters specificity, linearity, precision, and accuracy. The specificity test showed that there was no interference from excipients commonly found in the commercial pharmaceutical formulation at 331.4 nm. The standard curve showed a correlation coefficient of 0.9997. Precision was demonstrated by a relative standard deviation value of 0.50%. The recovery test resulted in an average of 100.06%, which confirmed the accuracy of the method. The results for first-derivative spectrophotometry (D(1)), liquid chromatography, and micellar electrokinetic chromatography were compared by analysis of variance (ANOVA), and there were no significant differences among these methods. Therefore, D(1) can be easily and directly applied to analyze RSG in coated tablets.