The irradiation of phenothiazines derivates thioridazine (TR), trifluoperazine (TFP)and fluphenazine (FP) generate their excited states and radical species that potentially might cause damage in biological molecules, including cytochrome c (cyt c), a mitochondrial protein fundamental to the cell respiration and apoptosis trigerring and/or regulation. In the present work, we investigated the dual effect of the excited state of phenothiazines on the spin state and reactivity of cyt c modulated by the aggregation state of the drugs. Cyt c was submitted to UV-irradiation at 254 nm during 120 min, in the absence and in the presence of the phenothiazines: TR, TFP and FP tested over a concentration range from 0.005 to 2.5 mM, at pH 4.0 and over a pH range from 7.0 to 3.0 with 0.025 and 2.5 mM drugs. At pH 4.0, in the absence of drugs, the irradiation promoted the cyt c Soret band shift from 409 to 406 nm with initial rate of 0.42 ms^-1. At pH 4.0, up to 0.0025mM, phenothiazines amplified and accelerated the cyt c damage (Soret band peak = 405 nm and blue shift initial rate = 0.6 ms^-1). Above 0.0025 mM, increasing TR concentrations progressively protected cyt c against UV light (Sorte band = 407 nm and blue shift initial rate = 0.23 ms^-1 with 2.5 mM TR). The presence of 0.0025 mM drug slightly protected cyt c from pH 7.0 to 5.0 and progressively increased the damage from pH 4.5 to 3.0. The conversion of cyt c to the high spin form (cytc405) was attested by UV-vis spectrophotometry, EPR and MCD measurements. MALDI-ToF was spectrometry of cytc405 revealed oxidation of Met65, Met80 and Tyr74. Thus, the predominance of phenothiazine-promoted cyt c damage or protection is dependent of a balance among the yield of photogenerated drug cation radicals, which is favored by acidic pH, the stability of the cation radicals, which is favored by the drug aggregation and the cyt c structure, modulated by the pH. Supported by FAPESP, CNPq and FAEP-UMC.