A novel flow injection-chemiluminescence (FI-CL) approach is proposed for the assay of pioglitazone hydrochloride (PG-HCl) based on its enhancing influence on the tris(2,2 '-bipyridyl)ruthenium(II)-silver(III) complex (Ru(bipy)(3)(2+)-DPA) CL system in sulfuric acid medium. The possible CL reaction mechanism is discussed with CL and ultraviolet (UV) spectra. The optimum experimental conditions were found as: Ru(bipy)(3)(2+), 5.0 x 10(-5) M; sulfuric acid, 1.0 x 10(-3) M; diperiodatoargentate(III) (DPA), 1.0 x 10(-4) M; potassium hydroxide, 1.0 x 10(-3) M; flow rate 4.0 ml min(-1) for each flow stream and sample loop volume, 180 mu l. The CL intensity of PG-HCl was linear in the range of 1.0 x 10(-3) to 5.0 mg L-1 (R-2 = 0.9998, n = 10) with limit of detection [LOD, signal-to-noise ratio (S/N) = 3] of 2.2 x 10(-4) mg L-1, limit of quantification (LOQ, S/N = 10) of 6.7 x 10(-4) mg L-1, relative standard deviation (RSD) of 1.0 to 3.3% and sampling rate of 106 h(-1). The methodology was satisfactorily used to quantify PG-HCl in pharmaceutical tablets with recoveries ranging from 93.17 to 102.77 and RSD from 1.9 to 2.8%.