Degradation of PPCPs by AOPs has gained major interest in the past decade. In this work, theophylline (TP) oxidation was studied in thermally (TAP) and chemically (CAP) activated persulfate systems, separately and in combination (TCAP). For [TP]₀ = 10 mg L⁻¹, (i) TAP resulted in 60% TP degradation at [PS]₀ = 5 mM and T = 60 °C after 60 min of reaction and (ii) CAP showed slight degradation at room temperature; however, (iii) TCAP resulted in complete TP degradation for [PS]₀ = [Fe²⁺]₀ = 2 mM at T = 60 °C following a pseudo-first order reaction rate with calculated k_obs = 5.6 (±0.4) × 10⁻² min⁻¹. In the TCAP system, the [PS]₀ : [Fe²⁺]₀ ratio of 1 : 1 presented the best results. A positive correlation was obtained between the TP degradation rate and increasing temperature and [PS]₀, and a negative correlation was obtained with increasing pH. Both chloride and humic acid inhibited the degradation process, while nitrates enhanced it. TP dissolved in spring, sea and waste water simulating real effluents showed lower degradation rates than in DI water. Waste water caused the highest inhibition (k_obs = 2.6 (±0.6) × 10⁻⁴ min⁻¹). Finally, the TCAP system was tested on a real factory effluent highly charged with TP, e.g. [TP]₀ = 160 mg L⁻¹, with successful degradation under the conditions of 60 °C and [PS]₀ = [Fe²⁺]₀ = 50 mM.