: Health-related quality of life (QoL) represents important measure of treatment outcome in mental disorders. Numerous studies indicate that QoL of people with schizophrenia and bipolar disorder is similar to that of patients with chronic physical conditions. It has been shown that schizophrenia patients can themselves reliably assess their QoL; in addition to the objective scales various self-reporting instruments are used. Patients with bipolar disorder have QoL consistently higher than patients with schizophrenia and similar to that found in people with unipolar depression. Quality of life can be negatively affected by drug-induced side-effects and subjective treatment response. The second-generation antipsychotics (SGA) have superior efficacy on QoL over classical antipsychotics in approximately half of the studies with schizophrenia; in the other half those groups are comparable. However, in none of the trials novel antipsychotics were inferior. All SGA (clozapine, olanzapine, risperidone, amisulpride, quetiapine, ziprasidone, or remoxipride) have been found to be beneficial for patients well-being. The most investigated drugs that convincingly improve QoL in schizophrenia are olanzapine and risperidone (including depot form). Results of several studies indicate that individual antipsychotics may differ in their effects on QoL, with suggested superiority of olanzapine. In bipolar disorder, SGA consistently showed their superiority over placebo in effects on QoL. The most studied SGA in bipolar disorder is olanzapine. More long-term controlled double-blind trials are needed to definitively uphold superiority and different effects of individual SGA on QoL of patients with schizophrenia and bipolar disorder.