Spain and Romano grew up in the Roman Empire. Following the disappearance of Ancient Rome, Austria and France fought over the ownership of Italy. Austria won and kept Veneziano (Romano's brother, North Italy), while Romano was given to Spain.
Romano proved to be a challenge to look after. However, Spain refused to give his servant to France when he asked for him. Later, Spain begged Austria to exchange Veneziano for Romano due to the former being more obedient and cuter, but Austria refused. Romano felt jealous of how his brother got more attention and felt that Spain was simply using him to claim some of his grandfather's inheritance. Spain was unaware of this and believed that Romano hated him.
When Romano was kidnapped by Turkey, Spain rescued his servant. He later spent a lot of money to protect Romano from Turkey, as Romano had become "special" to him. This made Romano see how much Spain truly cared for him, and Spain also started viewing Romano as cuter.
Romano was under Spain's rule for a long time. During this time, Romano rebelled against his boss, but after getting taken over by Austria, he came to the conclusion that Spain was better. Since then, Spain and Romano had had a good relationship.
Even long after Romano had left Spain and moved to live with his brother in their homeland, Romano stayed in contact with Spain. Whenever he got into trouble, he called Spain for help, such as when he and his brother were kidnapped by England during the Spanish Civil War.
During the modern era, Spain and Romano were often seen together.
Spamano is a popular ship, and the most popular pairing for both characters. Some believe that Romano treats Spain coldly because he fears that Spain only wants him for his grandfather's inheritance. Some speculate that Romano is a strong Catholic, and he hides his homosexuality/bisexuality due to it not being approved by his religion.