The high-performance liquid chromatographic retention parameters (k) have been determined for a series of 29 phenothiazines and related drugs. The k values were obtained on a hydrocarbon-bound silica stationary phase, an aminopropyl stationary phase and an aminopropyl phase coated with melanin. Polycratic retention data determined on a hydrocarbonaceous column were extrapolated to 0% of organic modifier in binary aqueous eluent yielding the chromatographic hydrophobicity parameter, log k'w. Logarithms of capacity factors determined isocratically on the aminopropyl column were subtracted from analogous values obtained with the same column loaded with melanin. The resulting parameter, log k'm-a, in combination with log k'w produced a regression equation (correlation coefficient r = 0.9531, significance level p = 10(-6)) which could be used to describe drug-melanin binding efficiency, EB. Theoretical EB values were calculated by means of the derived equation for the whole series of 29 drugs chromatographed. The efficiency of binding EB to synthetic melanin was also determined by an ultrafiltration method for fifteen members of the series. No statistically significant differences were observed between the EB values calculated using the chromatographic and ultrafiltration approaches. The results indicate that chemometric analysis of the appropriate chromatographic data is a practical method for the evaluation of melanin binding.