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The church contains a 25 cm-high icon of the Virgin Mary dated by style and dendrochronology to the 11th century, though it had previously been claimed by tradition to have appeared miraculously in 524 at the table of Galla, a Roman woman who was helping the poor, and then carried in processions since 590. It was previously housed in the now-demolished Oratory of Santa Gala, sited at what is now the piazza's far end near the Porticus Octaviae (giving the church and icon its name of "Madonna of the Portico").
The icon was believed to have saved the city from plague in 1656 (or 1658), when it was carried in procession through the streets. On account of this, the earlier church on this site was replaced by Pope Alexander VII between 1659 and 1667 with the present one, designed by Carlo Rainaldi in the high Baroque style.
The present church has a travertine façade with large columns against (but not attached to) it, thus giving it strong vertical lines. The original design included statues which were however never executed.
The interior shrine of Our Lady was created to contain the icon at the same date (to a design by the Maltese artist Melchiorre Caffà, or by Giovanni Antonio de Rossi), with a "gloria" (an architectural use of light for dramatic effect as used in Bernini's statue of St. Peter in the Basilica of St Peter of 1666). There is a staircase behind the 'gloria' allowing a better view of the icon, open by request only.
The first chapel on the right has a St Michael by Sebastiano Conca. The second has a Saints Anne, Joseph, and Mary by Luca Giordano. The angels are by Michel Maille, Francesco Cavallini, and Francesco Baratta. In the right crossing is the funerary monument of Cardinal Bartolomeo Pacca (died 1863), sculpted by Ferdinando Pettrich. The main altar (of 1667), designed by Rainaldi, completed by Antonio De Rossi, Ferrata and Giovanni Paolo Schor, enshrines the image of Our Lady mentioned above. In the third chapel to the left, a Conversion of St Paul by Ludovico Gimignani, in the first chapel on the left, The Holy Family and Beata Ludovica Albertoni by Lorenzo Ottoni. At left is Chapel of St. John the Baptist, which contains the funerary monument to Cardinal Paluzzo Paluzzi Altieri degli Albertoni, sculpted by Giuseppe Mazzuoli.
Since the time of the James Francis Edward Stuart, the church has been a centre of devotion for the conversion of England.
List of Cardinal Protectors 
- Vincenzo Costaguti (1643-1652)
- Benedetto Pamphilj (1681–1685)
- Melchior de Polignac (1724)
- Giacomo Lanfredini (1734–1741)
- Henry Stuart (1747–1759)
- Flavio Chigi (1759–1771)
- Filippo Carandini (1787–1794)
- Charles Erskine (1803–1811)
- Stanislao Sanseverino (1816–1825)
- Belisario Cristaldi (1828–1831)
- Adriano Fieschi (1838–1843)
- Lodovico Altieri (1845–1860)
- Francesco Pentini (1863–1869)
- Bartolomeo Pacca, Jr. (1875–1880)
- Francesco Ricci Paracciani (1882–1891)
- Francesco Segna (1894–1911)
- Giovanni Lugari (1911–1914)
- Francis Aidan Gasquet, OSB (1915–1929)
- Massimo Massimi (1935–1954)
- Carlo Chiarlo (1958–1964)
- Charles Journet (1965–1975)
- Corrado Bafile (1976–2005)
- Andrea Cordero Lanza di Montezemolo (2006–present)
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