Background A growing number of studies have shown that thiazolidinedoniones(TZD) can be antipsoriatic. Pioglitazone is a representative of the class of antidiabetic drugs known as TZD. TZD can activate nuclear peroxisome proliferator-activated receptors (PPAR)-c. PPARs are expressed on epidermal keratinocytes and exert their effects by promoting the terminal differentiation of keratinocytes, inhibiting epidermal growth, and reducing inflammatory responses. These observations suggest that TZD have potential benefits in the treatment of cutaneous and metabolic pathologies associated with psoriasis. Objective A systematic review and meta-analysis was carried out to evaluate the efficacy of combined Pioglitazone treatment. We point out 3 controversial side effects from administration of Pioglitazone in psoriasis: elevated liver enzymes, weight gain, and nausea. Study selection Randomized, single blind, or double blind, published studies of Pioglitazone compared with placebo, given to patients with plaque psoriasis for 10 weeks or 12 weeks were considered for inclusion in this review. The primary outcomes were 75% or greater improvement in the Psoriasis Area and Severity Index score from baseline (PASI 75) with pioglitazone. Data collection and analysis The systematic literature search was conducted in the PubMed, Embase, Google Scholar, and Cochrane databases from inception up to December20, 2018. Data analysis was done using Revman 5.3. Main results We included 6 studies(3 publications of pioglitazone only; 3 publications of pioglitazone combination therapy) comprising a total of 294 patients (n = 149 with pioglitazone only and n = 145 with pioglitazone combination therapy) in the analysis. There was a significantly PASI 75 response, in the pioglitazone only subgroup as compared to placebo(OR =8.74, 95% CI 3.76-20.31, P < 0.00001), and the pioglitazone combination subgroup as compared to placebo(OR =4.64, 95% CI 2.03-10.60, P < 0.00001), others, the total of pioglitazone as compared to placebo(OR =6.37, 95% CI 3.55-11.43, P < 0.00001), And tests of subgroup differences show: p = 0.29, I2 = 9.5%. The incidence rate of elevated liver enzymes (OR =3.70, 95% CI 0.56-24.31, P =0.99), weight gain(OR =1.44, 95% CI 0.60-3.47, P =0.41) and nausea(OR =0.76, 95% CI 0.23-2.49, P =0.65) were not significantly different compared with the control group. Conclusion Pioglitazone has efficacy for the treatment of plaque psoriasis. There is no significant difference between patients treated with Pioglitazone only or in combination with other therapies. The incidence rate of side effects associated with Pioglitazone treatment such as elevated liver enzymes, weight gain, and nausea were not significantly different compared with the control group.